METABOTROPIC GABA[B] RECEPTORS, RECEPTOR-SPECIFIC LIGANDS AND THEIR USES

Abstract: The present invention provides purified GABAB receptors and receptor proteins derived from rat and human sources, as well as nucleic acids which encode such proteins. The proteins and nucleic acids of the invention share significant homology with the GABAB receptor and the DNA encoding it as specifically disclosed herein. The invention moreover provides methods for isolating other members of the GABAB receptor family using DNA cloning technology and probes derived from the sequences provided herein, as well as novel members of the GABAB receptor family isolated by such methods. Furthermore, the invention relates to the use of GABAB receptors and receptor proteins and cells transformed with a gene encoding a GABAB receptor protein in a method for identifying and characterising compounds which modulate the activity of the GABAB receptor, such as GABAB receptor agonists and antagonists, which may be useful as pharmacological agents for the treatment of disorders associated with the central and peripheral nervous systems.

Description: METABOTROPIC GABAfB] RECEPTORS, RECEPTOR-SPECIFIC LIGANDS AND THEIR USES The present invention relates to nucleic acids encoding proteins of the GABA B receptor family, as well as proteins encoded thereby and the use of such proteins for the development of pharmacological agents. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter found in the brain and peripheral nervous system. Receptors for GABA have been divided into two subfamilies, the GABA A and GABA B receptors. Of these, GABA A receptors are involved in fast inhibitory signal transmission, whilst GABA B receptors appear to be involved in modulation of neurotransmission. Pre-synaptic GABA B receptors influence the release of neurotransmitters and neuropeptides such as GABA, glutamate, noradrenaline, dopamine, 5-hydroxytryptamine, substance P, cholecystokinin and somatostatin, while post-synaptic GABAB receptors are coupled to potassium channels via G proteins and mediate late inhibitory post-synaptic potentials (IPSPs). The effect of the activation of both subtypes of the GABA B receptor is to modulate synaptic transmission. GABA B receptors are located throughout the central and peripheral nervous systems (see Ong and Kerr, Life Sciences, (1990) 46, 1489-1501 ; Bowery era/., Drug Res. (1992) 42(1 ), 2a, 215-223), and are thus involved in the regulation of a wide variety of neurally- controlled physiological responses, from memory and learning to muscle contraction. This makes the GABA B receptor a target for pharmaceutical agents intended to treat central and peripheral neural disorders, and indeed a variety of GABA B agonists and antagonists are known and have been proposed for use in therapy (Bittiger et al., in GABA: Receptors, Transporters and Metabolism, Tanaka, C, and Bowery, N.G. (Eds). Birkhauser Verlag Basel/Switzerland (1996), 297-305; Bittiger et al., Trends Pharmacol. Sci., , 391 -394, 1993; Froestl era/., J. Med. Chem., 38, 3297-3312, 1995; Froestl et al., Ibid., 3313-3331). For example, in Alzheimer's disease and other dementias such as Age Associated Memory Impairment and Mύlti Infarct Dementia, loss of cognitive function is associated with reduced levels of a number of neurotransmitters in the brain. In particular, a deficit in L-glutamate is expected to " cause a major loss of cognitive functions, since L-glutamate appears to be crucially involved in the processes underlying memory formation and learning. GABA acts directly at many synapses to reduce the release of L-glutamate by acting on GABA B hetero- receptors. Thus, GABA B receptor antagonists are indicated for the treatment of dementias, and indeed have been shown to improve cognitive functions in animal studies. In addition, GABA B receptor antagonists are expected to be active in psychiatric and neurological disorders such as depression, anxiety and epilepsy (Bittiger era/., 1993, 1996, Op. Cit.; Froestl etal., 1995, Op. Cit.). GABA B receptor agonists are known as antispastic agents, and in peripheral nervous system applications, agonists are expected to be beneficial in bronchial inflammation, asthma and coughing (Bertrand etal., Am. J. Resp. Crit. Care Med. 149, A900, 1994). GABA is moreover associated with activity in the intestine, the cardiovascular system, gall and urinary bladders, and a variety of other tissues (Ong and Kerr, Op. Cit.). GABA action in each of the above cases is known to be mediated by GABA B receptors, making the receptors targets for pharmacological agents designed to treat a number of disorders. Despite the advanced state of molecular biology and protein purification technology, and the evident desirability of obtaining a purified GABA B receptor for pharmacological studies, the GABA B receptor previously has not been cloned or purified to homogeneity. A previous report of its partial purification (Nakayasu etal., J. Biol. Chem., 268, 8658-8664, 1993) appears to have been inaccurate, relating to an 80 kDa protein, which we now know to be too small. In order to be able to clone the GABA B receptor, we have developed a number of GABA B receptor-specific ligands. By expression cloning using one such highly selective GABA B receptor ligand labelled to high specific radioactivity, we have now cloned different GABA B receptors from rat and human sources, sequenced them and expressed the respective recombinant receptors in mammalian cell culture. Summary of the Invention The present invention provides purified GABA B receptors and GABA B receptor proteins, as well as nucleic acids which encode such proteins. The proteins and nucleic acids of the invention share significant homology with the GABA B receptors and the DNAs encoding them as specifically disclosed herein. In particular, there are provided two GABA B receptor proteins designated GABA B R1a and GABA B R1b which are distinct variants of GABAB isolated from rat. The respective cDNA and derived amino acid sequences are set forth in SEQ ID Nos. 1 , 2, and 5, 6, respectively. Furthermore, there are provided two human GABA B receptor clones termed GABA B Rla/b (representing a partial receptor clone) and GABA B R1 b (representing a full-length receptor clone) isolated from human sources. The respective cDNA and derived amino acid sequences are set forth in SEQ ID Nos. 3, 4, and 7, 8, respectively. The GABAB receptors and GABA B receptor proteins of the invention show specific binding to one or more of the selective GABA B receptor antagonists of Formula I and Formula II: [" S I]CGP 62413 [ 1Z5 I]CGP 71872 The invention accordingly provides the compounds of Formula I and Formula II. Moreover, binding of the these selective GABA B receptor antagonists may be competed with other selective GABA B receptor agonists or antagonists, such as the compound of Formula III and Formula IV: The invention moreover provides methods for isolating other members of the GABA B receptor family using DNA cloning technology and probes derived from the sequences provided herein, as well as novel members of the GABA B receptor family isolated by such methods. Furthermore, the invention relates to the use of GABA B receptors and GABA B receptor proteins and cells transformed with a gene encoding such a GABA B receptor or receptor protein in a method for identifying and characterising compounds which modulate the activity of the GABA B receptor(s), such as GABA B receptor agonists and antagonists, which may be useful as pharmacological agents for the treatment of disorders associated with the central and peripheral nervous systems. In particular, GABA B receptor antagonists can e.g. be useful as cognition enhancers, nootropics, antidepressants and anxiolytics for the treatment of cerebral insufficiency, depression, anxiety, epilepsy of the petit mal type, schizophrenia and myopia, whereas GABA B receptor agonists can e.g. be useful in the treatment of disorders such as spasticity, trigeminal neuralgia, asthma, cough, emesis, ulcers, urinary incontinence and cocain addiction. Brief Description of the Figures Figure 1a depicts the expression of the recombinant GABA B R1 a receptor in COS1 cells. Membranes from rat cortex membranes (lane 1) and COS1 cells transfected with the GABA B R1a rat-cDNA (lanes 2 and 3) are labelled with the photoaffinity ligand [ 125 I]CGP 71872. Autoradiography of a 6% SDS gel with 25μg protein loaded per lane is shown. Lanes 1 and 2: Specific binding with 0.6nM [ 125 I]CGP 71872. Lane 3: Control experiment where specific binding with 0.6nM [ 125 I]CGP 71872 is competed with 1 μM of unlabeled CGP 54626A (an antagonist specific for GABA B receptors). The apparent molecular weight of native and recombinant GABA B receptors are estimated from gel mobilities relative to those of SDS-PAGE standards (BioRad). Figure 1 b additionally shows the results for COS1 cells transfected with the GABA B R1 b rat-cDNA (lane 3). Figure 2 shows the inhibition of [ 125 I]CGP 64213 binding to GABA B receptors in membranes from rat cerebral cortex (open symbols) and recombinant GABAβRI a receptors in membranes from COS 1 cells (closed symbols) by the GABA B receptor antagonists CGP 54626A (•), CGP 64213 (A) and CGP 35348 (■). Figure 3 shows the inhibition of [ 1Z5 I]CGP 64213 binding to GABA B receptors in membranes from rat cerebral cortex (open symbols) and recombinant GABA B R1a receptors in membranes from COS 1 cells (closed symbols) by the GABA B receptor agonists GABA (•), L-baclofen (A) and APPA 3-(aminopropyl-phosphinic acid )(■). Figure 4 shows photoaffinity crosslinking of GABA B receptor proteins. Cell membranes of the tissues indicated are photoaffinity-labelled with [ 125 I]CGP71872 and subjected to SDS-PAGE and autoradiography. a, b, Selectivity of the photoaffinity ligand [ 125 I]CGP71872. a, Differential distribution of GABA B receptor variants of 130K and 100K in tissues of the nervous system. [ 125 I]CGP71872 binding is inhibited by addition of 1 μM of CGP54626A, a selective GABA B receptor antagonist, o, Competition of [ 12S I]CGP71872 labelling by different ligands. Incubation of membrane extracts with the photoaffinity ligand is carried out in the presence of competitor substances at the concentrations indicated, c, GABA B receptors are N-glycosylated. Photoaffinity-labelled rat cortex cell membranes are incubated with 0.4 units N-glycosidase F or 0.6 milliunits O-glycosidase (Boehringer Mannheim), d, Photolabelling of GABA B receptors from different species. Brain tissues from the species indicated are labelled as described hereinbelow. In the case of Drosophila melanogaster and Haemonchus concortus whole animals are analysed. Figure 5 shows the results of assays concerning pharmacological properties of native and recombinant GABA B receptors. GABA B R1a mediates inhibition of adenylate cyclase. HEK293 cells stably expressing GABA B R1a are treated with 20 μM forskolin (Fsk) to stimulate cAMP formation (100%). Fsk induced cAMP accumulation is reduced significantly (2P < 0.001; Dunneti's /-test) upon simultaneous addition of 300 μM L-baclofen. The effect of L-baclofen is antagonised in the presence of 10 μM CGP54626A. Preincubation of the cells with 10 ng/ml pertussis toxin (PTX) for 15-20 h completely abolishes the effect of L-baclofen. No L-baclofen response is observed in non-transfected HEK293 cells (insert). Bars represent mean values +S.E.M. of at least three independent experiments performed in quadruplicate. Detailed Description of the Invention The invention relates to purified GABA B receptors and GABA B receptor proteins, nucleic acids coding therefore and various applications thereof. Before the present invention, the GABA B receptor has not been available in purified form, but only as crude membrane preparations. For the first time, the present invention enables the production of different but related GABA B receptors in a substantially purified form, by means of recombinant DNA technology. In general, it is expected that such proteins in glycosylated form will have an observed molecular weight " of between 100 and 130 kDa, whereas the unglycosylated forms will have an observed molecular weight of between 90 and 110 kDa, respectively. GABA B receptors according to the invention are G-protein coupled modulators of neurotransmitter activity which are responsive to GABA. They may be defined by binding to labelled ligands which are selective for GABA B receptors, in particular [ 125 I]CGP 62413 and [ 125 I]CGP 71872. Functional studies are moreover possible in which a recombinant GABA B receptor is expressed in cell systems containing G-proteins and effectors such as ionic channels which can be activated by GABA and GABA B receptor agonists. Proteins according to the invention may be defined electrophysiologically in transgenic or knockout animals, for example in terms of their responsiveness in assays for the GABA B receptor(s) which are known in the art, such as the measurement of late IPSPs (inhibitory post-synaptic potentials), paired-pulse inhibition or (-)-baclofen-induced depression of field EPSPs (excitatory post-synaptic potentials). GABA B receptors are responsible for the observation of IPSPs as a result of indirect coupling to potassium channels in neurons, so established agonists and antagonists of GABA B receptors may be used to determine the presence of GABA B receptors in neuronal preparations by assaying for their effect on IPSPs. Advantageously, however, GABA B receptor proteins according to the invention are assessed by their susceptibility to CGP64213 and CGP71872 as measured by paired-pulse widening of field EPSPs. Both said compounds abolish paired-pulse widening normally associated with GABA B receptors, since they are effective GABA B autoreceptor antagonists. Preferably, therefore, the activation of GABA B receptor proteins according to the invention is specifically inhibited by CGP64213 and CGP71872. Examples of specific inhibition by these compounds are set out hereinbelow. As used herein, the term "GABA B receptor(s)" refers to the proteins whose sequences are substantially those set forth in SEQ ID Nos. 2 and 8, while the term "GABA B receptor proteins" includes derivatives and variants such as e.g. splice variants thereof which are related structurally and/or functionally to the GABA B receptor(s). Preferred GABA B receptor proteins according to the invention are e.g. those set forth in SEQ ID Nos. 4 and 6, and share at least one common structural determinant with the GABA B receptors having the amino acid sequences set forth in SEQ ID Nos. 2 and 8, respectively. "Common structural determinant" means that the derivative in question comprises at least one structural feature of the GABA B receptors set out in SEQ ID Nos. 2 and 8. Structural features includes possession of an epitope or antigenic site that is capable of cross-reacting with antibodies raised against a naturally occurring or denatured GABA B receptor polypeptide or fragment thereof, possession of amino acid sequence identity with the GABA B receptor(s) and features having common a structure/function relationship. Thus the GABA B receptor proteins as provided by the present invention include amino acid mutants, glycosylation variants and other covalent derivatives of the GABA B receptor(s) which retain the physiological and/or physical properties of the GABA B receptor(s). Further included within the scope of the term "GABA B receptor proteins" are naturally occurring variants of the GABA B receptor(s) found within a particular species, preferably a mammal. Such a variant may be encoded by a related gene of the same gene family, by an allelic variant of a particular gene, or represent an alternative splicing variant of the GABA B receptor gene. Variants according to the invention have the same basic function as the GABA B receptor(s), but may possess divergent characteristics consistent with their nature as variants. For example, it is expected that the GABA B receptors are members of a family of GABA B receptor proteins, the isolation and characterisation of which is enabled for the first time by the present invention. Different members of the GABA B receptor family may be expected to have different activity profiles, possibly according to differences in their tissue- specific localisation and role in modulating neuronal signalling. Moreover, the present invention enables the isolation and characterisation of further GABA B receptors, GABA B receptor proteins and GABA B receptor protein-encoding nucleic acids from any species, including man. The provision of sequence data enables the person skilled in the art to apply standard hybridisation methodology, as is known in the art and set out by way of example hereiπbelow, to isolate any desired GABA B receptor-encoding nucleic acid. The invention further comprises derivatives of the GABA B receptor(s), which retain at least one common structural determinant of the GABA B receptor(s). For example, derivatives include molecules wherein the protein of the invention is covalently modified by substitution, chemical, enzymatic, or other appropriate means with a moiety other than a naturally occurring amino acid. Such a moiety may be a detectable moiety such as an enzyme or a radioisotope. Derivatives which retain common structural determinants can be fragments of the GABA B receptor(s). Fragments of the GABA B receptor(s) comprise individual domains thereof, as well as smaller polypeptides derived from the domains. Preferably, smaller polypeptides derived from the GABA B receptor(s) according to the invention define a single feature which is characteristic of the GABA B receptor(s). Fragments may in theory be almost any size, as long as they retain one feature of the GABA B receptor(s). Preferably, fragments will be between 5 and 600 amino acids in length. Longer fragments are regarded as truncations of the full-length GABA B receptor(s) and generally encompassed by the term "GABAB receptor(s)". Preferably, said fragments retain the functional activity of the GABA B receptor(s). Such fragments may be produced by persons skilled in the art, using conventional techniques, by removing amino acid residues from the GABA B receptor proteins of the invention which are not essential for a particular functional aspect of the GABA B receptor proteins. Determination of functional aspects of a GABA B receptor protein may be made employing pharmacological or electrophysiological assays as herein described, and particularly by assays which monitor the ability of the GABA B receptor protein to bind GABA or a GABA mimic, or to couple to G proteins. Derivatives of the GABA B receptor(s) also comprise mutants thereof, which may contain amino acid deletions, additions or substitutions, subject to the requirement to maintain at least one feature characteristic of the GABA B receptor(s). Thus, conservative amino acid substitutions may be made substantially without altering the nature of the GABA B receptor(s). Substitutions and further deletions may moreover be made to the fragments of GABA B receptor proteins comprised by the invention. GABA B receptor protein mutants may be produced from a DNA encoding a GABA B receptor protein which has been subjected to in vitro mutagenesis resulting e.g. in an addition, exchange and/or deletion of one or more amino acid encoding triplets. For example, substitutional, deletional or insertional variants of the GABA B receptor(s) can be prepared by recombinant methods and screened for immuno- or physiological crossreactivity with the native forms of the GABA B receptor(s). Mutations may be performed by any method known to those of skill in the art. Preferred, however, is site-directed mutagenesis of a nucleic acid sequence encoding the polypeptide of interest. A number of methods for site-directed mutagenesis are known in the art, from methods employing single-stranded phage such as M13 to PCR-based techniques (see "PCR Protocols: A guide to methods and applications", M.A. Innis, D.H. Gelfand, J.J. Sninsky, T.J. White (eds.). Academic Press, New York, 1990). Preferably, the commercially available Altered Site II Mutagenesis System (Promega) may be employed, according to the directions given by the manufacturer. The fragments, mutants and other derivatives of the GABA B receptor(s) preferably retain substantial homology with the GABA B receptor(s). As used herein, "homology" means that the two entities share sufficient characteristics for the skilled person to determine that they are similar in origin and function. Preferably, homology is used to refer to sequence identity. Thus, the derivatives of the GABA B receptor(s) preferably retain substantial sequence identity with the sequences set forth in SEQ ID Nos. 2 and 8, respectively. "Substantial homology", where homology indicates sequence identity, means more than 30% sequence identity, preferably more than 65% sequence identity and most preferably a sequence identity of 80% or more. According to a further aspect of the present invention, there are provided nucleic acids encoding GABA B receptors and GABA B receptor proteins (SEQ ID Nos. 1 ,7, and 3,5, respectively). In addition to being useful for the production of recombinant GABA B receptors and receptor proteins, these nucleic acids are also useful as probes, thus readily enabling those skilled in the art to identify and/or isolate nucleic acids encoding further members of the GABA B receptor family and variants thereof as set forth hereinbefore. In another aspect, the invention provides nucleic acid sequences that are complementary to, or are capable of hybridising to, nucleic acid sequences encoding the GABA B receptors or receptor proteins. Preferably, such nucleic acids are capable of hybridising under high or moderate stringency, as defined hereinbelow. Furthermore, nucleic acids according to the invention are useful in a method determining the presence of a GABA B receptor- or receptor protein-specific nucleic acid, said method comprising hybridising the DNA (or RNA) encoding (or complementary to) the GABA B receptor or receptor protein to test sample nucleic acid and determining the presence of the GABA B receptor- or receptor protein-specific nucleic acid. The invention also provides a method for amplifying a nucleic acid test sample comprising priming a nucleic acid polymerase (chain) reaction with nucleic acid (DNA or RNA) encoding a GABA B receptor or receptor protein, or a nucleic acid complementary thereto. Isolated GABA B receptor- or receptor protein-specific nucleic acids include nucleic acids that are free from at least one contaminant nucleic acid with which they are ordinarily associated in the natural source of GABA B receptor- or receptor protein-specific nucleic acids or in crude nucleic acid preparations, such as DNA libraries and the like. Isolated nucleic acids thus are present in other than in the form or setting in which they are found in nature. However, isolated GABA B receptor and receptor protein encoding nucleic acids include GABA B receptor- and receptor protein-specific nucleic acids in ordinarily GABA B receptor- or receptor protein-expressing cells, where the nucleic acids are in a chromosomal location different from that of natural cells or are otherwise flanked by different DNA sequences than those found in nature. In accordance with the present invention, there are provided isolated nucleic acids, e.g. DNAs or RNAs, encoding GABA B receptors and GABA B receptor proteins, particularly mammalian GABA B receptors and receptor proteins, such as e.g. human and rat GABA B receptors and receptor proteins, or fragments thereof. In particular, the invention provides DNA molecules encoding human and rat GABA B receptors or receptor proteins, or fragments thereof. By definition, such a DNA comprises a coding single stranded DNA, a double stranded DNA consisting of said coding DNA and complementary DNA thereto, or this complementary (single stranded) DNA itself. Exemplary nucleic acids encoding GABA B receptors and GABA B receptor proteins are represented in SEQ ID Nos. 1 , 7, and 3, 5, respectively. The preferred sequences encoding GABA B receptors and receptor proteins are those having substantially the same nucleotide sequence as the coding sequences in SEQ ID Nos. 1 , 3, 5 and 7, with the nucleic acids having the same sequence as the coding sequences in SEQ ID Nos. 1 , 3, 5 and 7 being most preferred. As used herein, nucleotide sequences which are substantially the same share at least about 90 % identity. However, in the case of splice variants having e.g. an additional exon sequence homology may be lower. The nucleic acids of the invention, whether used as probes or otherwise, are preferably substantially homologous to the sequences encoding the GABA B receptors or receptor proteins as shown in SEQ ID No. 1 , 3, 5 and 7. The terms "substantially" and "homologous" are used as hereinbefore defined with reference to the GABA B receptor polypeptides. Preferably, nucleic acids according to the invention are fragments of the GABA B receptor- or receptor protein-encoding sequences, or derivatives thereof as hereinbefore defined in relation to polypeptides. Fragments of the nucleic acid sequences of a few nucleotides in length, preferably 5 to 150 nucleotides in length, are especially useful as probes. Exemplary nucleic acids can alternatively be characterised as those nucleotide sequences which encode a GABA B receptor or receptor protein as hereinbefore defined and hybridise to the DNA sequences set forth in SEQ ID Nos. 1 , 3, 5 and/or 7, or a selected fragment of said DNA sequences. Preferred are such sequences encoding GABA B receptors or receptor proteins which hybridise under high-stringency conditions to the sequences of SEQ ID Nos. 1 , 3, 5 and/or 7. Stringency of hybridisation refers to conditions under which polynucleic acids hybrids are stable. Such conditions are evident to those of ordinary skill in the field. As known to those of skill in the art, the stability of hybrids is reflected in the melting temperature (T m ) of the hybrid which decreases approximately by 1 to 1.5°C with every 1% decrease in sequence homology. In general, the stability of a hybrid is a function of sodium ion concentration and temperature. Typically, the hybridisation reaction is performed under conditions of higher stringency, followed by washes of varying stringency. As used herein, high stringency refers to conditions that permit hybridisation of only those nucleic acid sequences that form stable hybrids in 1 M Na + at 65-68 °C. High stringency conditions can be provided, for example, by hybridisation in an aqueous solution containing 6x SSC, 5x Denhardt's, 1 % SDS (sodium dodecyl sulphate), 0.1 sodium pyrophosphate and, 0.1 mg/ml denatured salmon sperm DNA as non specific competitor. Following hybridisation, high stringency washing may be done in several steps, with a final wash (about 30 min) at the hybridisation temperature in 0.2 - 0.1 x SSC, 0.1 % SDS. Moderate stringency refers to conditions equivalent to hybridisation in the above described solution but at about 60-62°C. In that case the final wash is performed at the hybridisation temperature in 1 x SSC, 0.1 % SDS. Low stringency refers to conditions equivalent to hybridisation in the above described solution at about 50-52°C. In that case, the final wash is performed at the hybridisation temperature in 2x SSC, 0.1 % SDS. It is understood that these conditions may be adapted and duplicated using a variety of buffers, e.g. formamide-based buffers, and temperatures. Denhardt's solution and SSC are well known to those of skill in the art as are other suitable hybridisation buffers (see, e.g. Sambrook, et al., eds. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York or Ausubel, etal., eds. (1990) Current Protocols in Molecular Biology, John Wiley & Sons, Inc.). In particular, the skilled person will understand that the stringency of hybridisation conditions may be varied by altering a number of parameters, primarily the salt concentration and the temperature, and that the conditions obtained are a result of the combined effect of all such parameters. Optimal hybridisation conditions have to be determined empirically, as the length and the GC content of the probe also play a role. Nucleic acids according to the invention may moreover be designed to have quite different sequences from those of nucleic acids encoding GABA B receptors or receptor proteins as derived from natural sources, through exploitation of the degeneracy of the amino acid code. In most cases, a plurality of nucleotide triplets may be used to encode a given amino acid. Thus, an almost limitless number of nucleic acids which encode identical GABA B receptors or receptor proteins may be designed. Those which most differ from the sequence of the naturally occurring nucleic acid may be so different as to be unable to hybridise therewith. The invention thus specifically encompasses any nucleic acid which encodes a GABA B receptor or GABA B receptor protein as hereinbefore defined. Preferred are all nucleic acids which encode the sequences of the GABA B receptors and receptor proteins set forth in SEQ ID Nos. 2, 8, and 4, 6, respectively. Given the guidance provided herein, the nucleic acids of the invention are obtainable according to methods well known in the art. For example, a DNA of the invention is obtain¬ able by chemical synthesis, using polymerase chain reaction (PCR) or by screening a genomic library or a suitable cDNA library prepared from a source believed to possess GABA B receptor or receptor protein and to express it at a detectable level. Chemical methods for synthesis of a nucleic acid of interest are known in the art and include triester, phosphite, phosphoramidite and H-phosphonate methods, PCR and other autoprimer methods as well as oligonucleotide synthesis on solid supports. These methods may be used if the entire nucleic acid sequence of the nucleic acid is known, or the sequence of the nucleic acid complementary to the coding strand is available. Alternatively, if the target amino acid sequence is known, one may infer potential nucleic acid sequences using known and preferred coding residues for each amino acid residue. An alternative means to isolate a gene encoding GABA B receptor or receptor protein is to use PCR technology as described e.g. in section 14 of Sambrook et al., 1989. This method requires the use of oligonucleotide probes that will hybridise to a GABA B receptor- or receptor protein-specific nucleic acid. A nucleic acid encoding a GABA B receptor or receptor protein can be isolated by screening suitable cDNA or genomic libraries under suitable hybridisation conditions with a probe, i.e. a nucleic acid disclosed herein including oligonucleotides derivable from the sequences set forth in SEQ ID Nos. 1 , 3, 5 and 7. Suitable libraries are commercially available or can be prepared e.g. from cell lines, tissue samples, and the like. Libraries are screened with probes or analytical tools designed to identify the gene of interest or the protein encoded by it. For cDNA expression libraries suitable means include monoclonal or polyclonal antibodies that recognise and specifically bind to the GABA B receptor or GABA B receptor protein; oligonucleotides of about 20 to 80 bases in length that encode known or suspected GABA B receptor- or receptor protein-specific cDNA from the same or different species; and/or complementary or homologous cDNAs or fragments thereof that encode the same or a hybridising gene. Appropriate probes for screening genomic DNA libraries include, but are not limited to oligonucleotides, cDNAs or fragments thereof that encode the same or hybridising DNA; and/or homologous genomic DNAs or fragments thereof. Particularly preferred screening techniques include the hybridisation of a test sample of DNA (cDNA or genomic library) with a GABA B receptor- or receptor protein-specific cDNA (SEQ ID Nos. 1 , 3, 5, 7) under suitable hybridisation conditions. Either the full length or fragments of the GABA B receptor- or receptor protein-specific cDNA can be used as probes. Such screening is initially carried out under low-stringency conditions. Low stringency conditions are as hereinbefore defined, but may be varied by adjusting the temperature and ionic strength of the hybridisation solution. For example, suitable conditions comprise hybridisation at a temperature between 40°C and 60°C in 0.5M NaH 2 PO pH 7.2, 7% sodium dodecyl sulphate (SDS), 1% bovine serum albumin, 1 mM EDTA, with a washing step at 50°C or less in 2 x standard saline citrate (SSC, 20 x SSC contains 3M sodium chloride, 0.3M sodium citrate, pH 7.0), 0.1 % SDS. Preferably, hybridisation conditions will be selected which allow the identification of nucleotide sequences having at least 40% sequence homology with respect to the probe. Similar homology screening techniques useful for the identification and isolation of additional cDNAs and genes of the GABA B - receptor gene family are described in United States Patent Number 5,202,257, incorporated herein by reference. After low stringency hybridisation has been used to identify cDNA or genomic clones having a substantial similarity with the probe sequence, these clones are then subjected to moderate to high stringency conditions in order to identify those clones having particularly high level of homology with respect to the probe sequence. Further examples of high stringency conditions comprise a hybridisation temperature of about 60°C to 68°C using the above mentioned hybridisation solution. Washing conditions comprise 0.5 x SSC, 0.1% SDS or less at a temperature of about 65°C or less. In view of the identification of GABA B receptor- and receptor protein-specific cDNAs according to the invention, the compiled sequence information can be used to design a set of degenerate oligonucleotide primer sequences from the regions most conserved among members of the gene family. A mixture of such oligonucleotide primers can be used in the polymerase chain reaction (PCR) to amplify cDNAs or genomic segments from genes related to the already isolated GABA B receptor- and receptor protein-specific cDNAs. Subsequently, these segments can serve as probes for identifying further full-length cDNA clones using high stringency hybridisation conditions. Alternatively, antibodies derived against the GABA B receptors or GABA B receptor protein provided by the present invention can be used to purify and sequence related GABA B receptors and receptor proteins also recognised by the antibodies. Screening of libraries in order to isolate nucleic acids according to the invention may moreover be performed by expression screening. Such methodology is known to those skilled in the art, for example as set out in Sambrook etal. (Op. Cit.), but essentially comprises the incorporation of nucleic acid clones into expression vectors which are then screened using a ligand specific for the desired protein product. GABA B receptor- or receptor protein-specific ligands may be antibodies, as described hereinbelow, or specific GABA antagonists or agonists. Especially preferred are compounds such as CGP 64213, described hereinbelow. - As used herein, an oligonucleotide probe is preferably a single-stranded DNA or RNA that has a sequence of nucleotides that includes between 10 and 50, preferably between 15 and 30 and most preferably at least about 20 contiguous bases that are the same as (or the complement of) an equivalent or greater number of contiguous bases as set forth in SEQ ID Nos. 1 , 3, 5 and 7. The nucleic acid sequences selected as probes should be of sufficient length and sufficiently unambiguous so that false positive results are minimised. The nucleotide sequences are usually based on conserved or highly homologous nucleotide sequences or regions of the GABA B receptor or receptor protein. The nucleic acids used as probes may be degenerate at one or more positions. The use of degenerate oligonucleotides may be of particular importance where a library is screened from a species in which preferential codon usage in that species is not known. Preferred regions from which to construct probes include 5' and/or 3' coding sequences, sequences predicted to encode ligand binding sites, and the like. For example, either the full-length cDNA clones disclosed herein or fragments thereof can be used as probes. Preferably, nucleic acid probes of the invention are labelled with suitable label means for ready detection upon hybridisation. For example, a suitable label means is a radiolabel. The preferred method of labelling a DNA fragment is by incorporating α 32 P dATP with the Klenow fragment of DNA polymerase in a random priming reaction, as is well known in the art. Oligonucleotides are usually end-labelled with γ 32 P-labelled ATP and polynucleotide kinase. However, other methods (e.g. non-radioactive) may also be used to label the fragment or oligonucleotide, including e.g. enzyme labelling, fluorescent labelling with suitable fluorophores and biotinylation. After screening the library, for example with a portion of DNA including substantially the entire GABA B receptor- or receptor protein-encoding sequence or a suitable oligonucleotide based on a portion of said DNA, positive clones are identified by detecting a hybridisation signal; the identified clones are characterised by restriction enzyme mapping and/or DNA sequence analysis, and then examined, for example by comparison with the sequences set forth herein, to ascertain whether they include DNA encoding a complete GABA B receptor or receptor protein (i.e., if they include translation initiation and termination codons). If the selected clones are incomplete, they may be used to rescreen the same or a different library to obtain overlapping clones. If the library is genomic, then the overlapping clones may include exons and introns. If the library is a cDNA library, then the overlapping clones will include an open reading frame. In both instances, complete clones may be identified by comparison with the DNAs and deduced amino acid sequences provided herein. In order to detect any abnormality of endogenous GABA B receptor or receptor protein, genetic screening may be carried out using the nucleotide sequences of the invention as hybridisation probes. Also, based on the nucleic acid sequences provided herein antisense- type therapeutic agents may be designed. In particular reference thereto, it is to be noted that antisense oligonucleotides are based on oligonucleotide probes as hereinbefore defined, and included within the definition thereof. Such oligonucleotides, especially but not only when intended for use as antisense therapeutic agents, may comprise modifications to the oligonucleotide, for example by incorporation of unnatural nucleotide analogues and modifications to natural oligonucleotides. For example, the oligonucleotides may encompass an altered backbone, for example in the form of a phosphorothioate, modifications such as 2'-0-Methyl modifications, or may be in the form of peptide nucleic acids. It is envisaged that the nucleic acids of the invention can be readily modified by nucleotide substitution, nucleotide deletion, nucleotide insertion or inversion of a nucleotide stretch, and any combination thereof. Such mutants can be used e.g. to produce a GABA B receptor or receptor protein mutant that has an amino acid sequence differing from the GABAB receptor or receptor protein sequences as disclosed herein or as found in nature. Mutagenesis may be predetermined (site-specific) or random. A mutation which is not a silent mutation must not place sequences out of reading frames and preferably will not create complementary regions that could hybridise to produce secondary mRNA structure such as loops or hairpins. In still another aspect of the invention, the nucleic acids are DNA molecules and further comprise a replicable vector comprising the nucleic acid encoding the GABA B receptor or receptor protein operably linked to control sequences recognised by a host transformed by the vector. As used herein, vector (or plasmid) refers to discrete elements that are used to introduce heterologous DNA into cells for either expression or replication thereof. Selection and use of such vehicles is a routine matter for the person of ordinary skill in the art and is described, for example, in Sambrook et al., (1989) Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press. Many vectors are available, and selection of appropriate vector will depend on the intended use of the vector, i.e. whether it is to be used for DNA amplification or for DNA expression, the size of the DNA to be inserted into the vector, and the host cell to be transformed with the vector. Each vector contains various components depending on its function (amplification of DNA or expression of DNA) and the host cell for which it is compatible. The vector components generally include, but are not limited to, one or more of the following: an origin of replication, one or more marker genes, an enhancer element, a promoter, a transcription termination sequence and a signal sequence. Advantageously, a eukaryotic expression vector encoding a GABA B receptor or receptor protein will comprise a locus control region (LCR). LCRs are capable of directing high-level integration site independent expression of transgenes integrated into host cell chromatin, which is of importance especially where the GABA B receptor or receptor protein gene is to be expressed in the context of a permanently-transfected eukaryotic cell line in which chromosomal integration of the vector has occurred, in vectors designed for gene therapy applications or in transgenic animals. Suitable vectors for expression in eukaryotic host cells, including yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms, will also contain sequences necessary for the termination of transcription and for stabilising the mRNA. Such sequences are commonly available from the 5 1 and 3' untranslated regions of eukaryotic or viral DNAs or cDNAs. Furthermore the invention provides host cells transformed with such a vector and a method of using a nucleic acid encoding a GABA B receptor or receptor protein according to the invention to produce such a GABA B receptor or receptor protein, comprising expressing a GABAB receptor- or receptor protein-specific nucleic acid in a culture of the transformed host cells and, if desired, recovering the GABA B receptor or receptor protein from the host cell culture. In accordance with another embodiment of the present invention, there are provided cells containing the above-described nucleic acids. Such host cells such as prokaryote, yeast and higher eukaryote cells may be used for replicating DNA and producing GABA B receptor or receptor protein. Suitable prokaryotes include eubacteria, such as Gram-negative or Gram-positive organisms, such as E. coli, e.g. E. coli K-12 strains DH5a, MC1061/P3 and HB101 , or Bacilli. Further hosts suitable for GABA B receptor protein encoding vectors include eukaryotic microbes such as filamentous fungi or yeast, e.g. Saccharomyces cerevisiae. Higher eukaryotic cells include insect and vertebrate cells, particularly mammalian cells. In recent years propagation of vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are epithelial or fibroblastic cell lines such as Chinese hamster ovary (CHO) cells, COS cells, NIH 3T3 cells, HeLa cells or HEK293 cells. The host cells referred to in this disclosure comprise cells in in vitro culture as well as cells that are within a host animal. DNA may be stably incorporated into cells or may be transiently expressed using methods known in the art, such as those detailed in Sambrook etal., Op. Cit., or Ausubel et al., (1990) Current Protocols in Molecular Biology, John Wiley & Sons, Inc. The polypeptides according to the invention can advantageously be expressed in insect cell systems, including whole insects. Insect cell lines suitable for use in the method of the invention include, in principle, any lepidopteran cell which is capable of being transformed with an expression vector and expressing heterologous proteins encoded thereby. In particular, use of the Sf cell lines, such as the Spodoptera frugiperda cell line IPBL-SF-21 AE (Vaughn etal., (1977) In Vitro, 13, 213-217) is preferred. The derivative cell line Sf9 is particularly preferred. However, other cell lines, such as Tricoplusia n/368 (Kurstack and Marmorosch, (1976) Invertebrate Tissue Culture Applications in Medicine, Biology and Agriculture. Academic Press, New York, USA) may be employed. These cell lines, as well as other insect cell lines suitable for use in the invention, are commercially available (e.g. from Stratagene, La Jolla, CA, USA). Expression vectors suitable for use in the invention include all vectors which are capable of expressing foreign proteins in insect cell lines. In general, vectors which are useful in mammalian and other eukaryotic cells are also applicable to insect cell culture. Baculovirus vectors, specifically intended for insect cell culture, are especially preferred and are widely obtainable commercially (e.g. from Invitrogen and Clontech). Other virus vectors capable of infecting insect cells are known, such as Sindbis virus (Hahn et al., (1992) PNAS (USA) 89, 2679-2683). The baculovirus vector of choice (reviewed by Miller (1988) Ann. Rev. Microbiol. 42, 177-199) is Autographa californica multiple nuclear polyhedrosis virus, AcMNPV. Nucleic acids and/or proteins according to the invention may be used in methods for screening compounds of mixtures of compounds which are potential modulators of GABA B receptors, and thus potential pharmacological agents. For example, cells transformed with a gene encoding a GABA B receptor or receptor protein can be used in a cell-based screening assay, in which the response of the cell to the agents being tested is monitored. The response may be in the form of the activation of a reporter gene, a measurable pharmacological or electrophysiological change, or the like. Alternatively, purified GABA B receptors or receptor proteins according to the invention can be used in in vitro assays to screen for modulators of GABA B receptor activity. Likewise, compounds which are capable of modulating the expression of the GABA B receptor genes, thus regulating GABA B receptor activity, can be screened for using an expression system in which a test gene (which may be one of the GABA B receptor genes itself) is operably linked to the control sequences normally associated with the GABA B receptor gene. The invention moreover includes compounds identified by such screening assays and the use of such compounds for the treatment of conditions which are susceptible to treatment by GABA B receptor modulation as exemplified hereinbefore. In accordance with yet another embodiment of the present invention, there are provided antibodies specifically recognising and binding to one or more of the GABA B receptors or receptor proteins of the invention. For example, such antibodies can be generated against the GABA B receptors having the amino acid sequences set forth in SEQ ID Nos. 2 and 8. Alternatively, GABA B receptor proteins as set forth in SEQ ID Nos. 4 and 6 or GABA B receptor protein fragments (which may also be synthesised by in vitro methods) are fused (by recombinant expression or an in vitro peptidyl bond) to an immunogenic polypeptide and this fusion polypeptide, in turn, is used to raise antibodies against a GABA B receptor protein epitope. Anti-GABA B receptor or receptor protein antibodies may be recovered from the serum of immunised animals. Monoclonal antibodies may be prepared from cells from immunised animals in the conventional manner. The antibodies of the invention are useful for studying GABA B receptor protein localisation, screening of an expression library to identify nucleic acids encoding GABA B receptors or receptor proteins or the structure of functional domains, as well as for the purification of GABA B receptors or receptor proteins, and the like. Antibodies according to the invention may be whole antibodies of natural classes, such as IgE and IgM antibodies, but are preferably IgG antibodies. Moreover, the invention includes antibody fragments, such as Fab, F(ab') 2 , Fv and ScFv. Small fragments, such Fv and ScFv, possess advantageous properties for diagnostic and therapeutic applications on account of their small size and consequent superior tissue distribution. The antibodies according to the invention may be used in diagnostic and therapeutic applications. Accordingly, they may be altered antibodies comprising an effector protein such as a toxin or a label. Especially preferred are labels which allow the imaging of the distribution of the antibody in vivo. Such labels may be radioactive labels or radioopaque labels, such as metal particles, which are readily visualisable within an organism. Moreover, they may be fluorescent labels or other labels which are visualisable on tissue samples removed from organisms. Recombinant DNA technology may be used to improve the antibodies of the invention. Thus, chimeric antibodies may be constructed in order to decrease the immunogenicity thereof in diagnostic or therapeutic applications. Moreover, immunogenicity may be minimised by humanising the antibodies by CDR grafting [see European Patent Application 0 239 400 (Winter)] and, optionally, framework modification [see EP 0 239400 and Riechmann etal., Nature 332, 323-327, 1988]. Antibodies according to the invention may be obtained from animal serum, or, in the case of monoclonal antibodies or fragments thereof, produced in cell culture. Recombinant DNA technology may be used to produce the antibodies according to established procedure, in bacterial or preferably mammalian cell culture. The selected cell culture system preferably secretes the antibody product. Therefore, the present invention includes a process for the production of an antibody according to the invention comprising culturing a host, e.g. E. coli or a mammalian cell, which has been transformed with a hybrid vector comprising an expression cassette comprising a promoter operably linked to a first DNA sequence encoding a signal peptide linked in the proper reading frame to a second DNA sequence encoding said protein, and isolating said protein. The invention further concerns hybridoma cells secreting the monoclonal antibodies of the invention. The preferred hybridoma cells of the invention are genetically stable, secrete monoclonal antibodies of the invention of the desired specificity and can be activated from deep-frozen cultures by thawing and recloning. The invention also concerns a process for the preparation of a hybridoma cell line secreting monoclonal antibodies directed to a GABA B receptor or receptor protein, characterised in that a suitable mammal, for example a Balb/c mouse, is immunised with purified GABA B receptor or receptor protein, an antigenic carrier containing purified GABA B receptor or receptor protein or with cells bearing GABA B receptor or receptor protein, antibody-producing cells of the immunised mammal are fused with cells of a suitable myeloma cell line, the hybrid cells obtained in the fusion are cloned, and cell clones secreting the desired antibodies are selected. For example spleen cells of Balb/c mice immunised with cells bearing GABA B receptor or receptor protein are fused with cells of the myeloma cell line PAI or the myeloma cell line Sp2/0-Ag14, the obtained hybrid cells are screened for secretion of the desired antibodies, and positive hybridoma cells are cloned. The invention also concerns recombinant DNAs comprising an insert coding for a heavy chain variable domain and/or for a light chain variable domain of antibodies directed to the extracellular domain of GABA B receptor or receptor protein as described hereinbefore. By definition such DNAs comprise coding single stranded DNAs, double stranded DNAs consisting of said coding DNAs and of complementary DNAs thereto, or these complementary (single stranded) DNAs themselves. The invention also provides a transgenic non-human mammal which has been modified to modulate the expression of endogenous GABA B receptor or receptor protein. Preferably, the transgenic non-human mammal is a transgenic mouse. For example, therefore, a transgenic mouse may be designed in which GABA B receptor or receptor protein production is greatly reduced or eliminated, according to procedures established in the art (Mansour etal., Nature 336, 348-352, 1988). Alternatively, the transgenic mouse of the invention may express elevated levels of GABA B receptor or receptor protein, or may be subject to regulation of GABA B receptor or receptor protein expression in a developmentally or tissue-specific manner, or via control by exogenous agents. Study of such an animal provides insights into the importance of the GABA B receptors and receptor proteins in vivo. The invention is further described hereinbelow, for the purposes of illustration only, in the following Examples. Example 1 Synthesis of ligand CGP64213 The radioligand [ 125 I1CGP 64213, which is used to visualise GABA B receptors expressed in COS cells, is synthesised according to Scheme 1 , using the following reagents and conditions: (1) NaH, THF, rt, 3 h; 5-bromovaleronitrile, rt, 16 h; (2) Raney nickel, 4% NH 3 in EtOH, 45° C, 16 h; (3) /V-ethoxy-carbonylphtalimide, Na 2 C0 3 , H 2 0, CH 2 CI 2 , rt, 5h; (4) Me 3 SiCI, EtOH, CH 2 CI 2 (1 :9), rt, 17 h; (5) Me.SiCI, Et_N, THF, rt, 17 h; (f?)-epichlorohydrin, 10 mol% ZnCI 2 THF, 80° C, 17 h; HOAC, MeOH, rt, 17 h; (6) /-Pr 2 EtN, EtOH, 80° C, 7 d; (7) LiOH, EtOH, H 2 0 (1 :1), 100° C, 17 h; MeOH, H 3 P0 4 ; (8) cone. HCI, 100° C, 17 h; (9) APr 2 EtN, DMF, rt, 72 h; (10) Na' 5 l, phosphate buffer pH 7.4, H 2 0 2 , cat. lactoperoxidase, 30 min, RP- HPLC. Ethyl (1 ,1 -diethoxyethyl)phosphinate 1 , prepared according to Froestl, W., etal. J. Med. Chem. (1995), 38, 3297-3312, from phosphinic acid and triethylorthoacetate under catalysed by boron trifluoride diethyl etherate, is condensed with 5-bromovaleronitrile to give the oily cyano-derivative 2 (bp 164° C at 0.13 mbar), which is hydrogenated over Raney nickel in ethanol containing 4% of ammonia to give primary amine 3 (bp 150-160° C at 10" 4 mbar; Kugelrohr bath temperature). The amino-group in 3 is protected as pthalimide to give 4, which is now deprotected at the phosphinic acid moiety under very mild conditions to give monosubstituted phosphinic acid ester 5. On reaction with trimethylchlorosilane the penta- valent phosphinate ester 5 is converted into a very reactive silyated phosphonite, which reacts readily with (fτ)-epichlorohydrin under zinc chloride catalysis to produce chlorohydrin 7. Condensation with 1-(fl)-(+)-(3-cyanophenyl)-ethylamine 8, which itself is prepared via resolution of racemic (3-cyano-phenyl)-ethylamine with Λ/-acetly-L-leucine to separate 1-(S)- (+)-(3-cyanophenyl)-ethylamine (according to Pickard et al., J. Amer. Chem. Soc. (1990) 112, 5741-5747) and treatment of the remaining mother liquors with (-)-camphanic acid followed by three crystallisations, gives the aromatic nitrile-ester 9, which is hydrolysed to the mefa-benzoic acid derivative 10 with lithium hydroxide. Concomitant hydrolysis of the ethyl phophinate ester occurs. The pthalimide protecting group is removed by boiling with concentrated hydrochlorid acid overnight to give the key intermediate CGP 57604A([3-[1 - (rτ)-[[3-(5-aminopentyl)-hydroxyphosphinyl]-2-(S)-hydroxypropyl]amino]-ethyl]-benzoic acid hydrochloride). This is reacted with commercially available Λ/-hydroxysuccinimidyl-3-(4- hydroxyphenyl)-propionate 11 in DMF using Hϋnig's base to give intermediate 12, which is iodinated with sodium iodide (125 isotope) using hydroperoxide and catalytic amounts of lactoperoxidase to give the radioactive ligand [ 125 I]CGP 64213. Scheme 1 (3) 99% CGP 57604A [ 125 IJCGP 64213 Unlabelled CGP 64213 is prepared in a slightly different way: 3-(4-hydroxy-5- iodophenyl propionic acid 13 is prepared by iodination of 3-(4-hydroxy-phenyl)propionic acid according to Runeberg, J., Ada Chem. Scand. (1958), 12, 188-91. Λ/-hydroxy-succinimidyl- 3-(4-hydroxy-5-iodophenyl)propionate 14 (mp: 191-4° C) is prepared according to Scheme 2 in 73% yield. Condensation of CGP 57604A (Scheme 1) with 14 using Hϋnig's base in DMF at room temperature for 72 hours proceeded as reaction 9 of Scheme 1 to give non radioactive CGP 64213 (mp: 170-5° C, crystallised from acetone) in a yield of 53%. a Reagents and conditions: Λ/-hydroxysuccinimide, DCC, dioxane, rt, 16 h. Characterisation of radioligand ['"I] CGP 64213: Preparation of synaptic membranes from rat cerebral cortex Twenty male rats flϊf: R AI f (SPF)] of about 200 g body weight are used. The animals are decapitated, the brains removed, the cerebral cortices dissected and homogenised in 10 volumes of ice-cold 0.32 M sucrose, containing MgCl2 (1 mM) and K2HPO4 (1 mM), with a glass/Teflon homogeniser. The membranes are centrifuged at 1000 x g for 15 min, the pellet resuspended and the centrifugation repeated. The supernatants are pooled and centrifuged at 20000 x g for 15 min. The pellet is osmotically shocked by resuspension in 10 volumes H2O and kept on ice for 30 min. The suspension is centrifuged at 39000 x g, resuspended in Krebs-Henseleit buffer (20mM Tris, pH 7.4, 118mM NaCI, 5.6mM glucose, 1.2mM KH 2 P0 4 , 1.2mM MgS0 4 , 4.7mM KCI, 1.8mM CaCI 2 ), and kept for 2 days at -20°C. The membranes are thawed at room temperature, washed three times with Krebs-Henseleit buffer by centrifugation at 20000 x g for 15 min, left overnight at 4°C and washed again three times. The final pellet is resuspended with a glass/Teflon homogenise in 20 ml of the same buffer. 2 ml aliquots are frozen and stored in liquid nitrogen. Just before use membranes are thawed quickly in a water bath at 37°C and again washed by centrifugation at 20000 x g for 15 min with the same buffer three times. Binding assay and characterisation of radioligand Incubation with [ 125 I]CGP 64213, specific radioactivity for fresh material 2000 Ci/mmol, is performed in 0.2 ml Krebs-Henseleit-Tris buffer, pH 7.4, at 20°C for 90 min with 50μg cortex membrane protein as substrate. The incubation is terminated by filtration through GF/B Whatman glass fibre filters. Nonspecific binding is defined by 10 "6 M CGP 54626A and is 5% of total binding at a concentration of 2 nM. In saturation experiments with increasing concentrations of [ 12S I]CGP 64213 and with nonlinear least square fitting a dissociation constant K 0 of 2.66 nM is determined. In inhibition studies at a concentration of 0.1 nM [ 1ZS I]CGP 64213, L-baclofen showed an inhibition constant K< of 442 nM and the antagonist CGP 54626 A a Kι of 2.5 nM in good agreement with 's obtained with other GABAB receptor antagonist radioligands. Unlabelled CGP 64213 is found to be inactive at a concentration of 1 μM in assays for GABA A , benzodiazepine, kainate, AMPA, NMDA receptors, for the strychnine independent binding site at NMDA receptors, muscarinic cholinergic, α,- and α 2 - adrenergic, β-adrenergic, 5HT,, 5HT 2 , 5HT 3 , histamine,, histamine.,, adenosine, μ- opiate and substance P receptors. The compound is therefore selective for GABA B receptors. At a concentration of 0.1 nM of [ 12 I]CGP 64213 association and dissociation kinetics are measured. The halftime of association is 20 min at 20°C and the halftime of dissociation 40 min. The halftime of dissociation is increased to 4 hours by reduction of the temperature to 4°C. This slow off rate and the high specific radioactivity of [ ,25 I]CGP 64213 allows autoradiographic studies of receptor binding in COS cells as expression systems for GABA B receptors. Example 2 Preparation of photoaffinity ligand The photoaffinity ligand [ 125 I]CGP 71872, which is used to tag GABAβ receptors from rat cortex membranes and recombinant GABAβ receptors expressed in COS cells is synthesised according to Scheme 3: Commercially available Λ/-hydroxy-succinimidyl-4- azido-salicylate 15 is condensed with CGP 57604A to give intermediate 16, which is iodinated with sodium iodide 125 isotope using chloramine T to give an approximately 1 :1 mixture of the 5-iodo derivative [ 25 I]CGP 71872 and the 3-iodo-derivative [125|JCGP 72565. They are separated via reverse phase HPLC on a Vydac 218TP54 column (retention times: 16.4 and 17.4 minutes, respectively). Reagents and conditions are as follows: (1) CGP 57604A (Scheme 1), -Pr 2 EtN, DMF, rt, 70 h; (2) Na 125 l, chloramine T, 0.01 N NaOH, rt, 1 h; RP-HPLC. Scheme 3 [ 125 I]CGP 71872 r [1τ2»5.|]CGP 72565 Unlabelled CGP 71872 is prepared in a different way: Λ/-hydroxy-succinimidyl-4-azido- 5-iodo-salicylate 17 is prepared via iodination of 4-azidosalicylic acid and subsequent condensation with Λ/-hydroxy-succinimide (Scheme 4). Condensation of 17 with CGP 57604A (see Scheme 1 , reaction 9) proceeded in 57 % yield to give non radioactive CGP 71872 (mp: >190° C dec). Reagents and conditions as follows: (1) (1) Nai, 2N NaOH, chloramine T, rt, 88 h; (2) Λ/-hydroxysuccinimide, DCC, dioxane, rt, 16 h; Scheme 4 Characterisation of photoaffinity ligand [ 125 I]CGP 71872: Binding assay and characterisation of ligand Rat cortex membranes as described for the [ ,Ϊ5 I]CGP 64213 assay are used as substrates. Incubation with [ , 5 I]CGP 71872, specific radioactivity of fresh material 2000Ci/mmol, is performed in 0.2 ml Krebs-Henseleit buffer, pH 7.4, at 20°C for 90 min with 50 μg membrane protein as substrate The incubation is terminated by filtration through GF/C Whatman glass fibre filters. Nonspecific binding is defined by 10 "6 M CGP 54626 A and is 5% of total binding at a concentration of 2 nM of [ ,2S I]CGP 71872, In saturation experiments with increasing concentrations of [ 125 I]CGP 71872, and nonlinear last square fitting a dissociation constant K D of 3.1 nM is calculated. L-baclofen showed in inhibition experiments a K of 340 nM and the antagonist CGP 54 626 A showed a K, of 3.1 nM. Unlabelled CGP 64213 is found to be inactive at a concentration of 1μM in the same receptor assays as described for [ 1ZS I]CGP 64213 and is, therefore, also selective for GABA B receptors. At a concentration of 2 nM and at 20°C, the halftime for association is 5 min, the halftime of dissociation 10 min. The dissociation time at 8°C is much longer. Only 25% of radioligand dissociates after 120 min. Photoaffinity labelling of membranes Membranes from rat cerebral cortex and from COS1 cells transiently transfected with GABA B R1 a and GABA B R1 b rat-cDNA, respectively, suspended in Krebs-Henseleit-Tris buffer, pH 7.3, at a concentration of 4 mg protein/ml, are incubated in the dark with 0.6 nM [ 125 l] CGP 71872 for one hour at room temperature. The incubation is terminated by centrifugation at 20 000 x g for 10 min at 4°C. This step removed free unbound photoaffinity label. Under these conditions about 50% of the total radioactivity used bound to the receptors. The pellet is resuspended at a concentration of 4mg protein/ml in a polyethylene vial and illuminated with UV light (365 nm) for 3 min (24 W). The suspension is centrifuged at 20 000 x g for 10 min and resuspended at a concentration of 8mg/ml protein in buffer. When the labelling is performed in the presence of excess unlabelled GABA B receptor antagonist (10 '6 M CGP 54626A), no radioactivity is bound to the membranes. The labelled membranes could be stored at -80°C. The results are shown in Figures 1 a and 1 b. Additionally, [ 125 I]CGP71872 photoaffinity labelling of cortex, cerebellum and spinal cord cell membranes is analysed as outlined above and reveals that the two GABA β protein variants R1 a and R1 b are differentially expressed in the nervous system. In cerebellum the 100K protein is predominant over the 130K protein, whereas in spinal cord the 130K protein is more prevalent. In cortex tissue both proteins appear equally abundant. No proteins are labelled in tissues such as liver and kidney which are expected to lack GABA β receptors and therefore have been used as controls (see Figure 4a). Furthermore, native GABAβ receptors are photoaffinity-labelled in the presence of various competitor substances indicated in Figure 4b. Neither the GABA A selective ligands muscimol and bicuculline nor the GABAQ receptor agonist c/s-aminocrotonic acid (CACA) or the inhibitor of the GABA uptake system, SK&F89976A (Zuiderwijk, M., Veenstra, E., Lopes Da Silva, F. H. & Ghijsen, W. E. J. M. Effects of uptake carrier blockers SK&F89976-A and L-trans-PDC on in vivo release of amino acids in rat hippocampus. Eur. J. Pharmacol. 307, 275-282 (1996)), compete significantly for radioligand binding. In contrast, the GABA β receptor agonists GABA, APPA (3-aminopropyl-phosphinic acid) and L-baclofen compete with [ 125 I]CGP71872 for binding. As another known criterion, L-baclofen competes more potently than D-baclofen. The GABA B receptor antagonists CGP54626A, CGP35348 and the non-radioactive photoaffinity ligand are also effective displacers of [ 12 I]CGP71872 at native receptors. For all ligands tested, there is no visible difference in the displacement of [125|]CGP71872 at the 130K and 100K proteins, indicating a qualitatively similar binding pharmacology for the two receptors. Native GABA β receptors are N-glycosylated, as shown by the reduction in molecular weight to 110K and 90K, respectively, after cleavage with N-glycosidase F (Fig. 4c). No significant shift in molecular weight is detected after enzymatic treatment with O-glycosidase (Fig. 4c). Photoaffinity-labelled proteins of 130K and 100K are detectable in tissues from all vertebrate species analysed, including zebrafish (Fig. 4d), indicating that the two proteins and their antagonist binding site are highly conserved. The avian GABAβ receptor proteins exhibit molecular weights slightly higher than in other species, possibly reflecting differences in glycosylation and/or RNA splicing. No binding of the photoaffinity ligand to any protein can be detected in the fruitfly Drosophila melanogaster and the nematode Haemonchus concortus. Example 3 Synthesis of the GABAB antagonist ligand CGP 54626A: The ligand used for displacement experiments, CGP 54626A, is synthesised according to Scheme 5: Scheme 5 a 22 CGP 54626A a Reagents and conditions: (1) NaH, THF, rt, 3 h; bromomethylcyclohexane, reflux, 24 h; (2) Me 3 SiCI, EtOH, CH2CI2 (1 :9), rt, 24 h; (3) e3SiCI, EfeN, THF, rt, 24 h; (fl)-epichlorohydrin, 10 mol% ZnCl2 THF, 80° C, 17 h; HOAc, MeOH, rt, 17 h; (4) AP^EtN, EtOH, 80° C, 7 d; (5) cone. HCI, 100° C, 24 h. Ethyl (1 ,1 -diethoxyethyl)phosphinate 1, prepared according to Froestl et al., J. Med. Chem. (1995), 38, 3297-3312, from phosphinic acid and triethylorthoacetate catalysed by boron trifluoride diethyletherate, is condensed with bromomethylcyclohexane to give the oily derivative 18 (bp 85° C at 6 x 10 '4 mbar), which is deprotected at the phosphinic acid moiety under very mild conditions to give monosubstituted phosphinic acid ester 19 (bp 50° C at 3 x 10 '4 mbar). On reaction with trimethylchlorosilane the penta-valent phosphinate ester 19 is converted into a very reactive trivalent ethyl phosphonite, which reacted rapidly with {R)- eplchlorohydrin 6 when catalysed by zinc chloride to produce chlorohydrin 20. Condensation with 1-(S)-(-)-(3,4-dichlorophenyl)-ethylamine 21 , prepared via resolution of racemic 1 -(3,4-dichlorophenyl)-ethylamine with (+)-mandelic acid according to Mickel, EP 543780 A2, gave the corresponding secondary amine 22 as a 1 :1 mixture of diastereoisomers, which is hydrolysed by boiling with concentrated hydrochloric acid to give CGP 54626A. [ 3 H]CGP54626A is prepared in an analogous way (Scheme 6) by condensation of ethyl (1 ,1-diethoxyethyl)phosphinate 1 with 3,4-dehydro-cylohexylmethylbromide (prepared according to Yadav and Fallis, (1991) Can. J. Chem. 69, 779-789), preparation of the corresponding 3,4-dehydroderivative of CGP 54626A, i.e. CGP 54951 A, which is tritiated under very carefully controlled conditions to yield [ 3 H]CGP54626A. The compound is the first GABAs receptor antagonist radioligand which was characterised by Bittiger etal., Pharmacol. Commun. (1992), 2, 23. Scheme 6 a a Reagents and conditions: (1 ) NaH, THF, rt, 3 h; 3-4-dehydrobromo-methylcyclohexane, reflux, 24 h; (2) Me 3 SiCI, EtOH, CH 2 CI 2 (1 :9), rt, 24 h; (3) Me 3 SiCI, Et 3 N, THF, rt, 24 h; (R)- epichlorohydrin, 10 mol% ZnCI 2 THF, 80° C, 17 h; HOAc, MeOH, rt, 17 h; (4) /-Pr EtN, EtOH, 80° C, 4 d; (5) LiOH, EtOH, H 2 0, 100° C, 17 h; HCI, MeOH, rt, 1 h; (6) 3 H 2 , 5% Pd/C, HCI, MeOH, pH = 1 , rt, 15 min, prep. TLC. Example 4 Proof of functional activity of CGP 64213 and CGP 71872 as GABA,, receptor antagonists by in vitro electrophysiological measurements. Experiments are performed on 400 μm thick hippocampal slices obtained either from female Wistar COB rats (3-4 weeks old) or male rats Tif: RAI f (SPF) using standard techniques. In brief, rats are cervically dislocated prior to decapitation. The brain minus cerebellum is removed rapidly and placed in ice-cold artificial cerebrospinal fluid (ACSF). The hippocampus is carefully isolated and, using either a tissue chopper (Sorvall*) or a vibroslicer (Campden), transverse 400 μm thick slices are cut. The CA3 region of each slice is removed via a scalpel cut. This procedure is performed to eliminate changes in network function that can occur due to epileptiform bursting in area CA3. The resultant CA3- ectomized slices are placed on a nylon mesh at the interface of a warmed (32°C), perfusing (1 -2 ml.min "1 ) ACSF and an oxygen-enriched (95% 0 2 , 5% C0 2 ), humidified atmosphere. The standard perfusion medium comprised (mM): NaCI, 124; KCI, 3; NaHC0 3 , 26; NaH_P0 4 , 1.25; CaCI 2 , 2; MgS0 4 , 1 ; D-glucose, 10; and is bubbled with 95% 0 2 , 5% C0 2 . An Axoprobe or an Axoclamp-2 amplifier (Axon Instruments, Foster City, CA, USA) is used in bridge mode to make extracellular recordings from either stratum radiatυm or stratum oriens using 4 M NaCl-filled microtectrodes (2 - 5 MΩ). Intracellular recordings are made using 2 M potassium methylsulphate filled microelectrodes (60-100 M Ω). Digitised records are stored on the hard disk of an IBM-compatible PC for off-line analysis. Bipolar stimulating electrodes, made from 55 μm diameter insulated nickel-chromium wire, are positioned in stratum radiatum close to the recording electrode placed in either stratum radiatum or stratum oriens, to provide orthodromic monosynaptic activation of CA1 neurones (Davies et al. (1990) Journal of Physiology 424: 513). In every experiment stimuli comprise square- wave pulses (20-200 μs; 5-30 V) delivered homosynaptically at a fixed intensity. All drugs are administered via the perfusion medium. Data are presented as means ± standard error of the mean (S.E.M.) and statistical significance is assessed using Students .-tests, n values refer to the number of times a particular experiment is performed, each in a different slice taken from a different rat. GABA B autoreceptors Paired-pulse widening of field EPSPs is used to monitor the effects of CGP 71872 and CGP 64213 on GABAβ autoreceptors. Paired-pulse widening occurs when two stimuli are delivered at 5-10 Hz (interstimulus interval 100 - 200 ms); a stimulation protocol that does not release sufficient GABA to activate GABAB heteroreceptors which would, in any case, cause a depression rather than a facilitation of the second field EPSP. This phenomenon is also independent of postsynaptic GABAB receptors (Nathan etal. (1991) Exp. Brain Res. 84(3) 529-537). It is, however, occluded by blocking GABAA receptor- mediated IPSPs and is inhibited by GABAB receptor antagonists at concentrations that are required to block GABAB autoreceptors (Nathan et al. (1990), Brain Research 531: 55-65). (Note that these concentrations are 3-10 fold higher than those necessary to block postsynaptic GABAB receptors on both pyramidal neurones and inhibitory interneurones so ruling out an effect at these receptors). Paired-pulse widening of field EPSPs (fEPSPs) is a sensitive measure of GABAB autoreceptor activity. There is no precedent for any compound being effective in this test system and not in other assays of GABA B autoreceptor activity e.g., paired-pulse or (-)-baclofen-induced depression of IPSCs. Paired-pulse stimulation at an interstimulus interval of 200 ms caused a consistent widening of the second EPSP relative to the first EPSP. Thus, the area under the curve of the second fEPSP is 247 ± 17 % (in the CGP 64213 series of experiments) and 241 ± 21 % (in the CGP 71872 series of experiments) of the first fEPSP, respectively. In the presence of CGP 64213 (0.3 μM; n = 5) and CGP 71872 (1 μM; n = 3) this paired-pulse widening of EPSPs is abolished indicating the effectiveness of these compounds as antagonists of GABAB autoreceptors. GABA B heteroreceptors The effect of CGP 71872 on the depression of field EPSPs induced by bath application of (-)-baclofen is used as an assay for the effect of this compound on GABAB heteroreceptors located on glutamate afferent terminals. Although, under these conditions, (-)-baclofen will activate other populations of GABAB receptors (e.g., GABAB autoreceptors and postsynaptic GABAB receptors), in addition to GABAB heteroreceptors, activation of these receptors would tend to increase the size of the field EPSP rather than decrease it. As such, this method is a reasonable measure of activity at GABAB heteroreceptors. This method provides a more reliable and a quantitatively more repeatable method for activating GABAB heteroreceptors than that used by Isaacson et al. (1993) Neuron 332: 156-158, as it does not rely on physiologically released GABA to activate the heteroreceptors. This latter method is inherently variable due to the different concentrations of synaptically released GABA to which heteroreceptors are exposed in different preparations; a parameter that depends upon the level of GABA released, the distance between the release site and heteroreceptor, and the efficiency of GABA uptake sites. It is important to note, however, that, to date, no discrepancy between the results obtained using these two methods to study GABAB heteroreceptors has been documented for any compound tested. (-)-Baclofen (10 μM) had no significant effect on the presynaptic fibre volley of the field EPSP (100 ± 1% of control; P>0.05), recorded in stratum radiatum, but depressed the field EPSP slope and peak amplitude by 65 ± 6% and 76 ± 9%, respectively (n = 10). Maximum depression is obtained after a 5-10 min perfusion and persisted at this level for the duration of the agonist application. Addition of CGP 71872 (1 μM) to the perfusion medium reversed the depression in every experiment in which it is tested (n = 6; P<0.05). Similar results are obtained for field EPSPs recorded in stratum oriens (n = 3). In brain slices CGP 71872 had no significant effect on the peak amplitude, slope or presynaptic fibre volley of field EPSPs recorded in stratum radiatum {n = 4; Pi 0.05) or oriens (n = 3). Postsynaptic GABA B receptors The effect of CGP 71872 on the pharmacologically isolated late IPSP is used as a test system to evaluate the effect of CGP 71872 on postsynaptic GABAB receptors located on CA1 pyramidal neurones. There is a substantial literature (Froestl et al. (1995) Op. Cit.; Jarolimek etal. (1993) Neurosci. Lett. 154: 31 -34; Olpe etal. (1990) Clin. Neuropharmacol. 13 Suppl. 2,: 396; McCormick, (1990) J.Neurophysiol. 62/5: 1018; Lambert etal., (1989) Neurosci. Lett. 107: 125-128; Soltesz etal., (1989) Brain Research 479: 49-55; Mueller and Misgeld, (1989) Neurosci. Lett. 102: 229-234; Dutar and Nicoll, (1988) Nature322: 156-8; Karlsson, Pozza and Olpe, (1988) Eur. J. Pharmacol. 148: 485-486) which indicates that this IPSP is mediated by the synaptic activation of GABAβ receptors. In addition, this method has been used many times in the past and the data generated have always been consistent with that generated for antagonism of (-)-baclofen-induced hyperpolarisations; an approach that has also been adopted as an assay for activity at postsynaptic GABAB receptors. The effect of CGP 71872 is tested on a monosynaptically activated GABAB receptor- mediated late IPSP isolated using a combination of the ionotropic excitatory amino acid antagonists D-2-amino-5-phosphonopentanoate (AP5; 50μM) and 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX; 20 μM) and the GABAA receptor antagonist picrotoxin (50μM). In all neurones tested CGP 71872 (1 μM) abolished the late IPSP {n = 6) indicating that this compound is an antagonist of postsynaptic GABAB receptors. Example 5 cDNA library construction RNA is purified from cortex and cerebellum of 7 day old rats according to Chomczynski, P. & Sacchi, N. (1987) Anal. Biochem. 162, 156-159. Poly A(+) RNA is enriched by two passages over an oligo (dT) column (Boehringer Mannheim) as described (Maniatis, T., Fritsch, E.F. & Sambrook, J. (1982) Molecular cloning: A laboratory manual (Cold Spring Harbor Lab., Cold Spring Harbor, NY). Oligo (dT) primed double stranded cDNA is synthesised from 5 μg of poly A(+) RNA using a commercial cDNA synthesis system (Amersham). The reverse transcriptase supplied with the kit is replaced by the RNAseH(-) Superscript II reverse transcriptase (Gibco BRL). The cDNA solution is concentrated on Centricon-100 devices (Amicon), preabsorbed with tRNA, to a final volume of 100μl. Small cDNAs are removed by passage through a Chromaspin-1000 column (Clontech). BstXI adaptors (Invitrogen) are added using T4 DNA ligase (Boehringer Mannheim) and the cDNAs are size-fractionated on an agarose gel. cDNAs with sizes larger than 2kb are purified (Qiaex, Qiagen) and ligated into the BstXI sites of the expression vector pcDNAI (Invitrogen). An aliquot of the ligation mixture is transformed (BioRad Gene Pulser II) into electrocompetent MC1061/P3 E.coli cells. The complexity of the library is estimated to be 2 x 10 6 independent clones. The average insert size deduced from the analysis of 48 clones is 2.9kb (sizes ranging from 2.0kb to 6.6kb). Plasmids for the transfections of COS1 cells are isolated from bacterial colonies obtained after the initial round of cDNA transformation. Briefly, an aliquot of the cDNA library is transformed into electrocompetent MC1061/P3 E.coli cells and titrated by plating on agar plates. The cDNA library is divided into pools of approximately 2'000 colonies that are plated on 9cm agar plates and grown overnight at 37°C. The bacteria are scraped off the plates and plasmid DNA is prepared using ion exchange columns (Qiawell, Qiagen). Example 6 Transfection of COS cells with cDNA C0S1 cells are obtained from the American Type Culture Collection (ATCC) and grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 15μg/ml gentamycin (Gibco BRL) in a humidified atmosphere with 5% co 2 . Plasmid DNA from pools of independent bacterial colonies are introduced into COS1 cells using a modification of the standard DEAE-dextran transfection procedure. Briefly, one day before transfection 7.5 x 10 5 cells are seeded per 9cm dish. The next day the medium is removed and the cells are incubated 15 min in 10ml of phosphate buffered saline (PBS tablets, Gibco BRL). Afterwards, PBS is removed and 4ml of 1 mg/ml DEAE-dextran (Pharmacia) in PBS is added to the dish. After 9 min incubation at room temperature the cells are washed twice with 5ml of PBS each. The PBS is aspirated and 4μg plasmid DNA (derived from pools of 2O00 independent bacterial colonies) in 540μl PBS is added to the dish and the cells incubated with the DNA for 30 min at 37°C with occasional rocking. Subsequently 4ml of DMEM medium containing 10% NU-serum (Collaborative Research) and 80μM chloroquine (Sigma) is added. After 4 hrs incubation at 37°C the medium is removed and the cells are incubated 2 min in 10% (vol/vol) dimethyl sulfoxide (Merck) in PBS. The cells are rinsed with PBS, eel! culture medium is added to the culture dishes and the cells are grown for an additional 2 to 3 days. Example 7 Identification of GABA B receptor clone by ligand binding assay Pools of cDNAs (2000 independent clones each) are analysed for GABA B receptor expression, after transient transfection into COS1 cells, using a radioligand binding assay with iodinated CGP64213 (specific activity 2'000 Ci/mmol). Culture dishes with transfected COS1 cells are placed on ice and washed twice with 5ml each of ice-cold Krebs-Henseleit-Tris buffer (20mM Tris-CI pH 7.4, 1 18mM NaCI, 5!6mM glucose, 1.2mM KH 2 P0 4 , 1.2mM MgS0 4 , 4.7mM KCI, 1.8mM CaCI 2 ). Afterwards the cells are incubated with 0.2nM of 125 I-CGP 64213 in Krebs-Tris buffer (1 ml solution per 9cm dish). After 80 min incubation at room temperature the dishes are cooled on ice and washed twice for 5 min with 5ml of ice-cold Krebs-Tris buffer. Subsequently the dishes are air dried using a fan and the walls of the plates are removed. For autoradiography, the bottom of the plates are exposed, together with intensifying screens, to Kodak X-OMAT AR films for 2 to 3 weeks at -80°C. A total of 640,000 independent clones (320 individual pools) from the above mentioned cDNA library are screened. One pool yields a positive signal in the ligand binding assay. The plasmid DNA from this pool is re-transformed into electrocompetent MC1061/P3 cells. 10 plasmid pools from 500 colonies each are prepared, two of which rescreened positive in the binding assay. After 4 subsequent rounds of subdivisions of one of the two pools (SIB selection; McCormick, M. (1987) Methods Enzymol. 151 , 445-449) a single cDNA clone containing a 4376bp insert is identified. This first cDNA clone identified, originally referred to as F4, is designated GABA B R1a (SEQ ID No. 1). This cDNA clone encompasses a large open reading frame coding for a putative protein of 960 amino acids with a calculated molecular weight of 108kDa (SEQ ID No.2). According to von Heijne (von Heijne, G. (1986) Nυcl. Acids. Res. 14, 4683-4691) the first 16 amino acids encode with high probability a signal peptide that is absent in the mature protein. The calculated molecular weight of the predicted mature protein is 106kDa. Hydrophobicity analysis of the putative protein with the algorithm of Kyte and Dolittle (1982) J. Mol. Biol. 157, 105-132, using sequence analysis programs from the University of Wisconsin Genetics Computer Group (Devereux, etal., (1984) Nucl. Acids. Res. 12, 387-395) predicts, as expected for a cell surface receptor coupled to G-proteins, several membrane spanning regions. Putative N-glycosylation sites are found at amino acid positions 7, 67, 392, 423, 465, 485, 497 and 614 of the predicted mature protein as set forth in SEQ ID No. 2. Example 8 Assay of cloned GABAB receptor In order to isolate membranes containing the cloned GABA B receptor, culture dishes containing GABA B receptor-expressing COS cells are washed twice with Krebs-Henseleit- Tris buffer. Afterwards the cells are scraped off the dishes, homogenised in a glass-glass homogeniser- and centrifuged for 30 min at 4°C at 40O00 g. The homogenisation and centrifugation step is repeated once. The pellet is resuspended in buffer and stored in liquid nitrogen until further analysis. Membranes from COS1 cells transfected with the GABA B receptor cDNA (membranes derived in a similar manner from brain tissue are used for reference) are suspended in Krebs-Henseleit-Tris buffer at a concentration of approximately 1 mg/ml. The membranes are then incubated in the dark with 0.6nM 125 I-CGP 71872 for one hour at room temperature. In control experiments 1 μM of unlabeled CGP 54626A, a GABA B receptor specific antagonist, is included. The incubation is terminated by centrifugation at 20O00 g for 10 min at 4°C. The pellet is washed once in buffer to remove unbound from bound photoaffinity label. The pellet is resuspended in buffer and illuminated with UV light (365nm, 24W) for 3 min. The suspension is again centrifuged (20 min, 40O00 g). The pellet is washed in buffer, dissolved in SDS sample buffer and separated on a 6% SDS gel according to Laemmli, U.K (1970) Nature 227, 680-685. The gel is dried and, together with intensifying screens, exposed to Dupont Reflection NEF-495 X-ray films overnight. The protein expressed from the 4'376bp cDNA clone has an apparent molecular mass of about 120kDa (Figure 1 ). The apparent molecular weight of the recombinant GABA B receptor is estimated from gel mobility relative to those of SDS-PAGE standards (BioRad). The binding pharmacology of the GABA B R1a receptor expressed in COS1 cells is compared with the binding pharmacology of native GABA B receptors in rat cerebral cortex membranes. To that aim, the binding characteristics of the radioligand [ 125 I]CGP 64213 and the inhibition of this binding by selected GABA B receptor antagonists and agonists are compared. The dissociation constant K D for the GABA B R1 a receptor expressed in COS cells is determined to be 1.85 nM. The Koof GABA B receptors expressed in cortex membranes is determined to be 2.7 nM and thus is similar to the value obtained for the recombinant receptor. The IC εo values (Table 1) and the slopes of the inhibition curves (Figure 2) for the GABA B receptor antagonists CGP 54626A (Froestl etal., (1992) Pharmacol. Communications 2, 52-56), CGP 71872, CGP 64213 and CGP 35348 (Froestl etal., 1992) are very similar for recombinant and native receptors. The rank order of affinity for the agonists GABA, L-baclofen and CGP 27492 (aminophosphinic acid, APPA) is identical at recombinant and native receptors, however the agonist affinity is always significantly lower at the recombinant GABA B R1 a receptor (Figure 3, Table 1 ). It is known that GTP or its stable analogue Gpp(NH)p reduce the affinity of agonists at native GABA B receptors by decoupling the receptors from their G-proteins (Hill etal., (1984) J.Neurochem. 42, 652- 657). Therefore, the lower affinity of agonists at the recombinant receptor may reflect the fact that in COS cells the G-proteins that normally couple to GABA B receptors in brain cells are not available. We have determined that for rat cortex GABA B receptors the IC 50 value of L-baclofen is shifted from 170 nM to 10 μM in the presence of 300 μM Gpp(NH)p. Thus decoupling G-proteins from native GABAB receptors results in an IC S0 value comparable to the 34 μM obtained for the recombinant GABA B R1a receptor expressed in COS cells. In conclusion, the recombinant GABA B R1a receptor shows similar binding pharmacology as native GABA B receptors from rat cortex. Table 1. BINDING PHARMACOLOGY OF NATIVE AND RECOMBINANT GABA B RECEPTORS Inhibition of [ lia l]CGP 64213 binding by GABA B receptor antagonists and agonists Exampie 9 Use of the GABAβRIa receptor cDNA to clone related genes The rat GABA B R1a-receptor cDNA isolated (SEQ ID No. 1 ) is useful as a probe to identify and isolate additional cDNAs, genes and proteins of the GABA B -receptor gene family. It is also useful to identify and isolate cDNAs, genes and proteins of the GABA B - receptor gene family in other species, such as for example humans. In order to isolate a further rat clone (referred to as GABA B R1 b) and human GABA B receptor clones, the abovementioned rat library and a human fetal brain cDNA library (Clontech, Palo Alto, cat. No. HL3025s) are cross-hybridised with the GABA B R1a cDNA under suitable hybridisation conditions. The human library is an unidirectional oligo (dT)- primed library consisting of 1.2 x 10 6 independent cDNA clones inserted into the expression vector pcDNAI. The method of screening a plasmid library by colony hybridisation is described in Sambrook et al. (1989). The hybridisation probe used is a 32 P-labelled 1.3kb Pvull/Scal fragment corresponding to bases 1931 to 3264 of the GABA B R1a cDNA (SEQ ID No. 1). Hybridisation is in 0.5M NaH 2 P0 4 (pH 7.2), 7% SDS, 1 mM EDTA at 60°C overnight. Subsequent wash steps are for one hour at a final stringency of 0.5 x SSC, 0.1% SDS at 55 °C (rat library) or 2 x SSC, 0.1% SDS at 50°C (human library). Kodak X OMAT AR films are exposed to the membranes overnight at -80°C with intensifying screens. The X-ray films are aligned to the agar plates with the bacterial colonies and colonies containing cross- hybridising cDNA clones are isolated. The bacteria are replated on agar dishes and the colony hybridisation screen is repeated twice. The individual colonies obtained are further analysed by Southern blot hybridisation. Selected cDNA clones are analysed by sequencing and a 2,9 kb cDNA for rat GABA B R1b characterised (see SEQ ID No. 5). This cDNA encodes a protein of 844 amino acids (see SEQ ID No. 6). The mature GABA B R1 b differs from the former GABA B R1a in that the N-terminal 147 amino acid residues are replaced by 18 different residues. Presumably, these two GABA B receptor variants are derived from the same gene by alternative splicing. Those clones which are positive in screening the human library are also analysed by sequencing and reveal one clone termed GABA B R1a/b (see SEQ ID No. 3) with a partial sequence encoding a receptor protein of 793 amino acid residues (see SEQ ID No. 4), as well as another clone termed GABA B R1 b human (see SEQ ID No. 7) which represents a full-length cDNA encoding a human GABA B receptor having 844 amino acids (see SEQ ID No. 8). Example 10 GABA B receptors stably expressed in HEK293 cells negatively couple to adenylate cyclase GABAβ receptors are described to inhibit adenylate cyclase activity, stimulate phospholipase A 2 , activate K + -channels, inactivate voltage-dependent Ca + -channels and to modulate inositol phospholipid hydrolysis. As GABA β RIa and -b have identical sequence in all domains predicted to be intracellular they are expected to be able to couple to the same effector systems. Using rat cortical slice preparations, L-baclofen has been shown to reduce forskolin-stimulated cAMP accumulation by about 40 percent. The ability of GABA β RIa stably expressed in HEK293 cells to reduce forskolin-stimulated cAMP accumulation is analysed (Fig. 5). We chose concentrations of forskolin and L-baclofen that should produce a maximal effect. Forskolin stimulates cAMP levels in HEK293 cells to more than ten times over the basal level. Stimulation of recombinantly expressed GABA B receptors by co-addition of 300 μM L-baclofen reduces forskolin stimulated cAMP accumulation by approximately 30 percent. This inhibition is antagonised by CGP54626A, a GABA β receptor antagonist. The modulation of adenylate cyclase activity by GABAβRIa is sensitive to pertussis toxin, indicating that in HEK293 cells, which are deficient in G 0 , GABA β RIa couples to G j . As a control, L-baclofen does not inhibit forskolin-stimulated cAMP formation in untransfected HEK293 cells (Fig. 5). Deposition Data The GABAB receptor clone GABA B R1a derived from rat was deposited under the Budapest Treaty at the Deutsche Sammlung von Microorganismen und Zellkulturen GmbH (DSMZ), Mascheroder Weg 1 b, D-38124 Braunschweig, Germany, with an effective deposition date of 17th May 1996 under the accession number DSM 10689. The GABA B receptor clones GABA B R1 b derived from rat as well as GABA B R1 b derived from human sources were deposited under the Budapest Treaty at the Deutsche Sammlung von Microorganismen und Zellkulturen GmbH (DSMZ), Mascheroder Weg 1b, D-38124 Braunschweig, Germany, with an effective deposition date of 21th February 1997 under the accession numbers DSM 11422 and 11421 , respectively. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: NOVARTIS AG (B) STREET: SCHWARZWALDALLEE (C) CITY: Basel (E) COUNTRY: Switzerland (F) POSTAL CODE (ZIP): 4002 (G) TELEPHONE: +41 61 696 11 11 (H) TELEFAX: +41 61 696 79 76 (I) TELEX: 962 991 (ii) TITLE OF INVENTION: Novel Receptors (iii) NUMBER OF SEQUENCES: 8 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4376 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double .(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA to mRNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Rattus norvegicus (vii) IMMEDIATE SOURCE: (B) CLONE: GABABRla rat (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION:182..3061 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION:182..3061 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: GTGGGGTTTG CGGGTAGCGA TCGAGAAGGG GAGAGACCCC GGCCAGGCAG GAGCCTGGAT 60 TCCTGTGGAA GAAGAACAGG GGGAGGGGAA GCTGGAGGAC CGGGAGGGAG AACGGGGAGC 120 CGCGGCCGGG CCTGGGGCCT TGAGGCCCGG GGAGAGCCGC GGAGCGGGAC CGGCCGCCGA 180 G ATG CTG CTG CTG CTG CTG GTG CCT CTC TTC CTC CGC CCC CTG GGC 226 Met Leu Leu Leu Leu Leu Val Pro Leu Phe Leu Arg Pro Leu Gly 1 5 10 15 GCT GGC GGG GCG CAG ACC CCC AAC GCC ACC TCG GAA GGT TGC CAG ATT 274 Ala Gly Gly Ala Gin Thr Pro Asn Ala Thr Ser Glu Gly Cys Gin lie 20 25 30 ATA CAT CCG CCC TGG GAA GGT GGC ATC AGG TAC CGT GGC TTG ACT CGC 322 lie His Pro Pro Trp Glu Gly Gly lie Arg Tyr Arg Gly Leu Thr Arg 35 40 45 GAC CAG GTG AAG GCC ATC AAC TTC CTG CCT GTG GAC TAT GAG ATC GAA 370 Asp Gin Val Lys Ala lie Asn Phe Leu Pro Val Asp Tyr Glu lie Glu 50 55 60 TAT GTG TGC CGA GGG GAG CGC GAG GTG GTG GGG CCC AAG GTG CGC AAA 418 Tyr Val Cys Arg Gly Glu Arg Glu Val Val Gly Pro Lys Val Arg Lys 65 70 75 TGC CTG GCC AAC GGC TCC TGG ACG GAT ATG GAC ACA CCC AGC CGC TGT 466 Cys Leu Ala Asn Gly Ser Trp Thr Asp Met Asp Thr Pro Ser Arg Cys 80 85 90 95 GTC CGA ATC TGC TCC AAG TCT TAT TTG ACC CTG GAA AAT GGG AAG GTT 514 Val Arg lie Cys Ser Lys Ser Tyr Leu Thr Leu Glu Asn Gly Lys Val 100 105 110 TTC CTG ACG GGT GGG GAC CTC CCA GCT CTG GAT GGA GCC CGG GTG GAG 562 Phe Leu Thr Gly Gly Asp Leu Pro Ala Leu Asp Gly Ala Arg Val Glu 115 120 125 TTC CGA TGT GAC CCC GAC TTC CAT CTG GTG GGC AGC TCC CGG AGC GTC 610 Phe Arg Cys Asp Pro Asp Phe His Leu Val Gly Ser Ser Arg Ser Val 130 135 140 TGT AGT CAG GGC CAG TGG AGC ACC CCC AAG CCC CAC TGC CAG GTG AAT 658 Cys Ser Gin Gly Gin Trp Ser Thr Pro Lys Pro His Cys Gin Val Asn 145 150 155 CGA ACG CCA CAC TCA GAA CGG CGT GCA GTA TAC ATC GGG GCG CTG TTT 706 Arg Thr Pro His Ser Glu Arg Arg Ala Val Tyr lie Gly Ala Leu Phe 160 165 170 175 CCC ATG AGC GGG GGC TGG CCG GGG GGC CAG GCC TGC CAG CCC GCG GTG 754 Pro Met Ser Gly Gly Trp Pro Gly Gly Gin Ala Cys Gin Pro Ala Val 180 185 190 GAG ATG GCG CTG GAG GAC GTT AAC AGC CGC AGA GAC ATC CTG CCG GAC 802 Glu Met Ala Leu Glu Asp Val Asn Ser Arg Arg Asp lie Leu Pro Asp 195 200 205 TAC GAG CTC AAG CTT ATC CAC CAC GAC AGC AAG TGT GAC CCA GGG CAA 850 Tyr Glu Leu Lys Leu lie His His Asp Ser Lys Cys Asp Pro Gly Gin 210 215 220 GCC ACC AAG TAC TTG TAC GAA CTA CTC TAC AAT GAC CCC ATC AAG ATC 898 Ala Thr Lys Tyr Leu Tyr Glu Leu Leu Tyr Asn Asp Pro lie Lys lie 225 230 235 ATT CTC ATG CCT GGC TGT AGT TCT GTC TCC ACA CTT GTA GCT GAG GCT 946 lie Leu Met Pro Gly Cys Ser Ser Val Ser Thr Leu Val Ala Glu Ala 240 245 250 255 GCC CGG ATG TGG AAC CTT ATT GTG CTC TCA TAT GGC TCC AGT TCA CCA 994 Ala Arg Met Trp Asn Leu lie Val Leu Ser Tyr Gly Ser Ser Ser Pro 260 265 270 GCC TTG TCA AAC CGA CAG CGG TTT CCC ACG TTC TTC CGG ACG CAT CCA 1042 Ala Leu Ser Asn Arg Gin Arg Phe Pro Thr Phe Phe Arg Thr His Pro 275 280 285 TCC GCC ACA CTC CAC AAT CCC ACC CGG GTG AAA CTC TTC GAA AAG TGG 1090 Ser Ala Thr Leu His Asn Pro Thr Arg Val Lys Leu Phe Glu Lys Trp 290 295 300 GGC TGG AAG AAG ATC GCT ACC ATC CAA CAG ACC ACC GAG GTC TTC ACC 1138 Gly Trp Lys Lys lie Ala Thr lie Gin Gin Thr Thr Glu Val Phe Thr 305 310 315 TGA ACG CTG GAT GAC CTG GAG GAG CGA GTG AAA GAG GCT GGG ATC GAG 1186 Ser Thr Leu Asp Asp Leu Glu Glu Arg Val Lys Glu Ala Gly lie Glu 320 325 330 335 ATC ACT TTC CGA CAG AGT TTC TTC TCG GAT CCA GCT GTG CCT GTT AAA 1234 lie Thr Phe Arg Gin Ser Phe Phe Ser Asp Pro Ala Val Pro Val Lys 340 345 350 AAC CTG AAG CGT CAA GAT GCT CGA ATC ATC GTG GGA CTT TTC TAT GAG 1282 Asn Leu Lys Arg Gin Asp Ala Arg lie lie Val Gly Leu Phe Tyr Glu 355 360 365 ACG GAA GCC CGG AAA GTT TTT TGT GAG GTC TAT AAG GAA AGG CTC TTT 1330 Thr Glu Ala Arg Lys Val Phe Cys Glu Val Tyr Lys Glu Arg Leu Phe 370 375 380 GGG AAG AAG TAC GTC TGG TTC CTC ATC GGG TGG TAT GCT GAC AAC TGG 1378 Gly Lys Lys Tyr Val Trp Phe Leu lie Gly Trp Tyr Ala Asp Asn Trp 385 390 395 TTC AAG ACC TAT GAC CCG TCA ATC AAT TGT ACA GTG GAA GAA ATG ACC 1426 Phe Lys Thr Tyr Asp Pro Ser lie Asn Cys Thr Val Glu Glu Met Thr 400 405 410 415 GAG GCG GTG GAG GGC CAC ATC ACC ACG GAG ATT GTC ATG CTG AAC CCT 1474 Glu Ala Val Glu Gly His He Thr Thr Glu He Val Met Leu Asn Pro 420 425 430 GCC AAC ACC CGA AGC ATT TCC AAC ATG ACG TCA CAG GAA TTT GTG GAG 1522 Ala Asn Thr Arg Ser He Ser Asn Met Thr Ser Gin Glu Phe Val Glu 435 440 445 AAA CTA ACC AAG CGG CTG AAA AGA CAC CCC GAG GAG ACT GGA GGC TTC 1570 Lys Leu Thr Lys Arg Leu Lys Arg His Pro Glu Glu Thr Gly Gly Phe 450 455 460 CAG GAG GCA CCA CTG GCC TAT GAT GCT ATC TGG GCC TTG GCT TTG GCC 1618 Gin Glu Ala Pro Leu Ala Tyr Asp Ala He Trp Ala Leu Ala Leu Ala 465 470 475 TTG AAC AAG ACG TCT GGA GGA GGT GGT CGT TCC GGC GTG CGC CTG GAG 1666 Leu Asn Lys Thr Ser Gly Gly Gly Gly Arg Ser Gly Val Arg Leu Glu 480 485 490 495 GAC TTT AAC TAC AAC AAC CAG ACC ATT ACA GAC CAG ATC TAC CGG GCC 1714 Asp Phe Asn Tyr Asn Asn Gin Thr He Thr Asp Gin He Tyr Arg Ala 500 505 510 ATG AAC TCC TCC TCC TTT GAG GGC GTT TCT GGC CAT GTG GTC TTT GAT 1762 Met Asn Ser Ser Ser Phe Glu Gly Val Ser Gly His Val Val Phe Asp 515 520 525 GCC AGC GGC TCC CGG ATG GCA TGG ACA CTT ATC GAG CAG CTA CAG GGC 1810 Ala Ser Gly Ser Arg Met Ala Trp Thr Leu He Glu Gin Leu Gin Gly 530 535 540 GGC AGC TAC AAG AAG ATC GGC TAC TAC GAC AGC ACC AAG GAT GAT CTT 1858 Gly Ser Tyr Lys Lys He Gly Tyr Tyr Asp Ser Thr Lys Asp Asp Leu 545 550 555 TCC TGG TCC AAA ACG GAC AAG TGG ATT GGA GGG TCT CCC CCA GCT GAC 1906 Ser Trp Ser Lys Thr Asp Lys Trp He Gly Gly Ser Pro Pro Ala Asp 560 565 570 575 CAG ACC TTG GTC ATC AAG ACA TTC CGT TTC CTG TCT CAG AAA CTC TTT 1954 Gin Thr Leu Val He Lys Thr Phe Arg Phe Leu Ser Gin Lys Leu Phe 580 585 590 ATC TCC GTC TCA GTT CTC TCC AGC CTG GGC ATT GTT CTT GCT GTT GTC 2002 He Ser Val Ser Val Leu Ser Ser Leu Gly He Val Leu Ala Val Val 595 600 605 TGT CTG TCC TTT AAC ATC TAC AAC TCC CAC GTT CGT TAT ATC CAG AAC 2050 Cys Leu Ser Phe Asn He Tyr Asn Ser His Val Arg Tyr He Gin Asn 610 615 620 TCC CAG CCC AAC CTG AAC AAT CTG ACT GCT GTG GGC TGC TCA CTG GCA 2098 Ser Gin Pro Asn Leu Asn Asn Leu Thr Ala Val Gly Cys Ser Leu Ala 625 630 635 CTG GCT GCT GTC TTC CCT CTC GGG CTG GAT GGT TAC CAC ATA GGG AGA 2146 Leu Ala Ala Val Phe Pro Leu Gly Leu Asp Gly Tyr His He Gly Arg 640 645 650 655 AGC CAG TTC CCG TTT GTC TGC CAG GCC CGC CTT TGG CTC TTG GGC TTG 2194 Ser Gin Phe Pro Phe Val Cys Gin Ala Arg Leu Ti Leu Leu Gly Leu 660 665 670 GGC TTT AGT CTG GGC TAT GGC TCT ATG TTC ACC AAG ATC TGG TGG GTC 2242 Gly Phe Ser Leu Gly Tyr Gly Ser Met Phe Thr Lys He Trp Trp Val 675 680 685 CAC ACA GTC TTC ACG AAG AAG GAG GAG AAG AAG GAG TGG AGG AAG ACC 2290 His Thr Val Phe Thr Lys Lys Glu Glu Lys Lys Glu Trp Arg Lys Thr 690 695 700 CTA GAG CCC TGG AAA CTC TAT GCC ACT GTG GGC CTG CTG GTG GGC ATG 2338 Leu Glu Pro Trp Lys Leu Tyr Ala Thr Val Gly Leu Leu Val Gly Met 705 710 715 GAT GTC CTG ACT CTT GCC ATC TGG CAG ATT GTG GAC CCC TTG CAC CGA 2386 Asp Val Leu Thr Leu Ala He Trp Gin He Val Asp Pro Leu His Arg 720 725 730 735 ACC ATT GAG ACT TTT GCC AAG GAG GAA CCA AAG GAA GAC ATC GAT GTC 2434 Thr He Glu Thr Phe Ala Lys Glu Glu Pro Lys Glu Asp He Asp Val 740 745 750 TCC ATT CTG CCC CAG TTG GAG CAC TGC AGC TCC AAG AAG ATG AAT ACG 2482 Ser He Leu Pro Gin Leu Glu His Cys Ser Ser Lys Lys Met Asn Thr 755 760 765 TGG CTT GGC ATT TTC TAT GGT TAC AAG GGG CTG CTG CTG CTG CTG GGA 2530 Trp Leu Gly He Phe Tyr Gly Tyr Lys Gly Leu Leu Leu Leu Leu Gly 770 775 780 ATC TTT CTT GCT TAC GAA ACC AAG AGC GTG TCC ACT GAA AAG ATC AAT 2578 He Phe Leu Ala Tyr Glu Thr Lys Ser Val Ser Thr Glu Lys He Asn 785 790 795 GAC CAC AGG GCC GTG GGC ATG GCT ATC TAC AAT GTC GCG GTC CTG TGT 2626 Asp His Arg Ala Val Gly Met Ala He Tyr Asn Val Ala Val Leu Cys 800 805 810 815 CTC ATC ACT GCT CCT GTG ACC ATG ATC CTT TCC AGT CAG CAG GAC GCA 2674 Leu He Thr Ala Pro Val Thr Met He Leu Ser Ser Gin Gin Asp Ala 820 825 830 GCC TTT GCC TTT GCC TCT CTG GCC ATC GTG TTC TCT TCC TAC ATC ACT 2722 Ala Phe Ala Phe Ala Ser Leu Ala He Val Phe Ser Ser Tyr He Thr 835 840 845 CTG GTT GTG CTC TTT GTG CCC AAG ATG CGC AGG CTG ATC ACC CGA GGG 2770 Leu Val Val Leu Phe Val Pro Lys Met Arg Arg Leu He Thr Arg Gly 850 855 860 GAA TGG CAG TCT GAA ACG CAG GAC ACC ATG AAA ACA GGA TCA TCC ACC 2818 Glu Trp Gin Ser Glu Thr Gin Asp Thr Met Lys Thr Gly Ser Ser Thr 865 870 875 AAC AAC AAC GAG GAA GAG AAG TCC CGA CTG TTG GAG AAG GAA AAC CGA 2866 Asn Asn Asn Glu Glu Glu Lys Ser Arg Leu Leu Glu Lys Glu Asn Arg 880 885 890 895 GAA CTG GAA AAG ATC ATC GCT GAG AAA GAG GAG CGC GTC TCT GAA CTG 2914 Glu Leu Glu Lys He He Ala Glu Lys Glu Glu Arg Val Ser Glu Leu 900 905 910 CGC CAT CAG CTC CAG TCT CGG CAG CAA CTC CGC TCA CGG CGC CAC CCC 2962 Arg His Gin Leu Gin Ser Arg Gin Gin Leu Arg Ser Arg Arg His Pro 915 920 925 CCA ACA CCC CCA GAT CCC TCT GGG GGC CTT CCC AGG GGA CCC TCT GAG 3010 Pro Thr Pro Pro Asp Pro Ser Gly Gly Leu Pro Arg Gly Pro Ser Glu 930 935 940 CCC CCT GAC CGG CTT AGC TGT GAT GGG AGT CGA GTA CAT TTG CTT TAC 3058 Pro Pro Asp Arg Leu Ser Cys Asp Gly Ser Arg Val His Leu Leu Tyr 945 950 955 AAG TGAGGGGGCA TGGAGAAGGA TCAAGCCAGT AGGGGAGGGA AGGGTCTGGG 3111 Lys 960 AAGAGGGTGG GGGCCTGGGA GGAGGGTAAG GACTCCTATC TCCAACCTGG AGAGCACACG 3171 CTCCAATCCC CCTCTTATAA ATACATGTCG CTCTGTGCAT CTGGGGTTAT TTGGGTCTCC 3231 AGTACTCTGG GAAACAGACT GTTTTCTTTC TCCCCTATAA TTTTATATCT CCACTTCACA 3291 GGTTTTGTTT GAACCCTGCT TGGAGTTATT ATTCACTCAT GGCTCCAGAG GGGCATCTCA 3351 TTTTTCTCCG GTAGCCTGTC TTGTACAGTT ACCACAGCAA CTCCTGTCAT TTCAGCAGCA 3411 GGGGTCTTCC TACACTAGCA GGGCTCTCGC TCTCTCCATT TTTCAGCCTC AGAATCTCCT 3471 TCCATTATTC TTCTCCTTCT ACATGTCTCC ATGGCTTCCT CTCCCAGGGG ACTCGTTCTA 3531 CACACATACA CACACACACA CACACACACA CACACACACA CACACACACA CACCCCGCAT 3591 CGTGCCCTCT CCTAGGCAGC TGCATGTCGT CCTGTACAAA TGTGCTCGCT TCTGAGTGCT 3651 TTGTGCGGCC GTTCACTTGT GCTGTCTGCA TAAGCTGCGT CTGTGAGTGC ACGGTGGTTT 3711 GTGGGTGCGT GAAGTGGCAT GCTCCGGTAG GTGTGTATGA TGCGTTGAGC ACGCTACGCT 3771 GTCTCCCTCA TGTGCACGCA TTGTGTCTGC TTATGTTTTA CTTGTATGCC TCTGTGTACT 3831 GTGTGTGTGT GTGTGTGTGC CCACGCGTGC GCCCGTGTGC ATGCGTTCGT GTTGCCCTGA 3891 CTGGCTGTCT CAGCCTTCTG AGTAATTGGG ATTCCAGTTG TCTGTCTAGC TCATGTCCTG 3951 TCTTCTTCCA GTAGAGCCGT GAACACCCAA CACACACAGT TAATCGGGCT CCCCCCAGTC 4011 CATGTTTTCT GAGCCATCCA AAAACTCTCC TTGGCCTTAG GTTCATCTAC AAATGTTCCC 4071 TCTGTTCTTT GCTCTCGTGC GTCCACCTTC ATTCTCTTCA GTCATTTCTC AGATCTGCTG 4131 CGTCGTGGTT TCCTTTCCTT CATTATCATC GTCATTATTT TTCAGAACTT AAGGGAAAAA 4191 GAAATGGGGA CAGGTTGGAG GCTGTTTCCA GTGGAATAGT GGGTGCGCGT CCTGACCAAA 4251 TGAAGGCACG GACAGATGGA CTGACGGGGC GGGAGGCGGC GTCCCTTTCA CACTGTGGTG 4311 TCTCTTGGGG GGGAAGGATC TCCCTGAATC TCAATAAAGC AGTGAACAGT AAAAAAAAAA 4371 AAAAA 4376 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 960 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein - (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Met Leu Leu Leu Leu Leu Val Pro Leu Phe Leu Arg Pro Leu Gly Ala 1 5 10 15 Gly Gly Ala Gin Thr Pro Asn Ala Thr Ser Glu Gly Cys Gin He He 20 25 30 His Pro Pro Trp Glu Gly Gly He Arg Tyr Arg Gly Leu Thr Arg Asp 35 40 45 Gin Val Lys Ala He Asn Phe Leu Pro Val Asp Tyr Glu He Glu Tyr 50 55 60 Val Cys Arg Gly Glu Arg Glu Val Val Gly Pro Lys Val Arg Lys Cys 65 70 75 80 Leu Ala Asn Gly Ser Trp Thr Asp Met Asp Thr Pro Ser Arg Cys Val 85 90 95 Arg He Cys Ser Lys Ser Tyr Leu Thr Leu Glu Asn Gly Lys Val Phe 100 105 110 Leu Thr Gly Gly Asp Leu Pro Ala Leu Asp Gly Ala Arg Val Glu Phe 115 120 125 Arg Cys Asp Pro Asp Phe His Leu Val Gly Ser Ser Arg Ser Val Cys 130 135 140 Ser Gin Gly Gin Trp Ser Thr Pro Lys Pro His Cys Gin Val Asn Arg 145 150 155 160 Thr Pro His Ser Glu Arg Arg Ala Val Tyr He Gly Ala Leu Phe Pro 165 170 175 Met Ser Gly Gly Trp Pro Gly Gly Gin Ala Cys Gin Pro Ala Val Glu 180 185 190 Met Ala Leu Glu Asp Val Asn Ser Arg Arg Asp He Leu Pro Asp Tyr 195 200 205 Glu Leu Lys Leu He His His Asp Ser Lys Cys Asp Pro Gly Gin Ala 210 215 220 Thr Lys Tyr Leu Tyr Glu Leu Leu Tyr Asn Asp Pro He Lys He He 225 230 235 240 Leu Met Pro Gly Cys Ser Ser Val Ser Thr Leu Val Ala Glu Ala Ala 245 250 255 Arg Met Trp Asn Leu He Val Leu Ser Tyr Gly Ser Ser Ser Pro Ala 260 265 270 Leu Ser Asn Arg Gin Arg Phe Pro Thr Phe Phe Arg Thr His Pro Ser 275 280 285 Ala Thr Leu His Asn Pro Thr Arg Val Lys Leu Phe Glu Lys Trp Gly 290 295 300 Trp Lys Lys He Ala Thr He Gin Gin Thr Thr Glu Val Phe Thr Ser 305 310 315 320 Thr Leu Asp Asp Leu Glu Glu Arg Val Lys Glu Ala Gly He Glu He 325 330 335 Thr Phe Arg Gin Ser Phe Phe Ser Asp Pro Ala Val Pro Val Lys Asn 340 345 350 Leu Lys Arg Gin Asp Ala Arg He He Val Gly Leu Phe Tyr Glu Thr 355 360 365 Glu Ala Arg Lys Val Phe Cys Glu Val Tyr Lys Glu Arg Leu Phe Gly 370 375 380 Lys Lys Tyr Val Trp Phe Leu He Gly Trp Tyr Ala Asp Asn Trp Phe 385 390 395 400 Lys Thr Tyr Asp Pro Ser He Asn Cys Thr Val Glu Glu Met Thr Glu 405 410 415 Ala Val Glu Gly His He Thr Thr Glu He Val Met Leu Asn Pro Ala 420 425 430 Asn Thr Arg Ser He Ser Asn Met Thr Ser Gin Glu Phe Val Glu Lys 435 440 445 Leu Thr Lys Arg Leu Lys Arg His Pro Glu Glu Thr Gly Gly Phe Gin 450 455 460 Glu Ala Pro Leu Ala Tyr Asp Ala He Trp Ala Leu Ala Leu Ala Leu 465 470 475 480 Asn Lys Thr Ser Gly Gly Gly Gly Arg Ser Gly Val Arg Leu Glu Asp 485 490 495 Phe Asn Tyr Asn Asn Gin Thr He Thr Asp Gin He Tyr Arg Ala Met 500 505 510 Asn Ser Ser Ser Phe Glu Gly Val Ser Gly His Val Val Phe Asp Ala 515 520 525 Ser Gly Ser Arg Met Ala Trp Thr Leu He Glu Gin Leu Gin Gly Gly 530 535 540 Ser Tyr Lys Lys He Gly Tyr Tyr Asp Ser Thr Lys Asp Asp Leu Ser 545 550 555 560 Trp Ser Lys Thr Asp Lys Trp He Gly Gly Ser Pro Pro Ala Asp Gin 565 570 575 Thr Leu Val He Lys Thr Phe Arg Phe Leu Ser Gin Lys Leu Phe He 580 585 590 Ser Val Ser Val Leu Ser Ser Leu Gly He Val Leu Ala Val Val Cys 595 600 605 Leu Ser Phe Asn He Tyr Asn Ser His Val Arg Tyr He Gin Asn Ser 610 615 620 Gin Pro Asn Leu Asn Asn Leu Thr Ala Val Gly Cys Ser Leu Ala Leu 625 630 635 640 Ala Ala Val Phe Pro Leu Gly Leu Asp Gly Tyr His He Gly Arg Ser 645 650 655 Gin Phe Pro Phe Val Cys Gin Ala Arg Leu Trp Leu Leu Gly Leu Gly 660 665 670 Phe Ser Leu Gly Tyr Gly Ser Met Phe Thr Lys He Trp Trp Val His 675 680 685 Thr Val Phe Thr Lys Lys Glu Glu Lys Lys Glu Trp Arg Lys Thr Leu 690 695 700 Glu Pro Trp Lys Leu Tyr Ala Thr Val Gly Leu Leu Val Gly Met Asp 705 710 715 720 Val Leu Thr Leu Ala He Trp Gin He Val Asp Pro Leu His Arg Thr 725 730 735 He Glu Thr Phe Ala Lys Glu Glu Pro Lys Glu Asp He Asp Val Ser 740 745 750 He Leu Pro Gin Leu Glu His Cys Ser Ser Lys Lys Met Asn Thr Trp 755 760 765 Leu Gly He Phe Tyr Gly Tyr Lys Gly Leu Leu Leu Leu Leu Gly He 770 775 780 Phe Leu Ala Tyr Glu Thr Lys Ser Val Ser Thr Glu Lys He Asn Asp 785 790 795 800 His Arg Ala Val Gly Met Ala He Tyr Asn Val Ala Val Leu Cys Leu 805 810 815 He Thr Ala Pro Val Thr Met He Leu Ser Ser Gin Gin Asp Ala Ala 820 825 830 Phe Ala Phe Ala Ser Leu Ala He Val Phe Ser Ser Tyr He Thr Leu 835 840 845 Val Val Leu Phe Val Pro Lys Met Arg Arg Leu He Thr Arg Gly Glu 850 855 860 Trp Gin Ser Glu Thr Gin Asp Thr Met Lys Thr Gly Ser Ser Thr Asn 865 870 875 880 Asn Asn Glu Glu Glu Lys Ser Arg Leu Leu Glu Lys Glu Asn Arg Glu 885 890 895 Leu Glu Lys He He Ala Glu Lys Glu Glu Arg Val Ser Glu Leu Arg 900 905 910 His Gin Leu Gin Ser Arg Gin Gin Leu Arg Ser Arg Arg His Pro Pro 915 920 925 Thr Pro Pro Asp Pro Ser Gly Gly Leu Pro Arg Gly Pro Ser Glu Pro 930 935 940 Pro Asp Arg Leu Ser Cys Asp Gly Ser Arg Val His Leu Leu Tyr Lys 945 950 955 960 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2620 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA to mRNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (vii) IMMEDIATE SOURCE: (B) CLONE: GABABRla/b human (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION:1..2379 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION:1..2379 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: GCA GTG TAC ATC GGG GCA CTG TTT CCC ATG AGC GGG GGC TGG CCA GGG 48 Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly Trp Pro Gly 1 5 10 15 GGC CAG GCC TGC CAG CCC GCG GTG GAG ATG GCG CTG GAG GAC GTG AAT 96 Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu Asp Val Asn 20 25 30 AGC CGC AGG GAC ATC CTG CCG GAC TAT GAG CTC AAG CTC ATC CAC CAC 144 Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu He His His 35 40 45 GAC AGC AAG TGT GAT CCA GGC CAA GCC ACC AAG TAC CTA TAT GAG CTG 192 Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu Tyr Glu Leu 50 55 60 CTC TAC AAC GAC CCT ATC AAG ATC ATC CTT ATG CCT GGC TGC AGC TCT 240 Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly Cys Ser Ser 65 70 75 80 GTC TCC ACG CTG GTG GCT GAG GCT GCT AGG ATG TGG AAC CTC ATT GTG 288 Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn Leu He Val 85 90 95 CTT TCC TAT GGC TCC AGC TCA CCA GCC CTG TCA AAC CGG CAG CGT TTC 336 Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg Gin Arg Phe 100 105 110 CCC ACT TTC TTC CGA ACG CAC CCA TCA GCC ACA CTC CAC AAC CCT ACC 384 Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His Asn Pro Thr 115 120 125 CGC GTG AAA CTC TTT GAA AAG TGG GGC TGG AAG AAG ATT GCT ACC ATC 432 Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He Ala Thr He 130 135 140 CAG CAG ACC ACT GAG GTC TTC ACT TCG ACT CTG GAC GAC CTG GAG GAA 480 Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp Leu Glu Glu 145 150 155 160 CGA GTG AAG GAG GCT GGA ATT GAG ATT ACT TTC CGC CAG AGT TTC TTC 528 Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin Ser Phe Phe 165 170 175 TCA GAT CCA GCT GTG CCC GTC AAA AAC CTG AAG CGC CAG GAT GCC CGA 576 Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin Asp Ala Arg 180 185 190 ATC ATC GTG GGA CTT TTC TAT GAG ACT GAA GCC CGG AAA GTT TTT TGT 624 He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys Val Phe Cys 195 200 205 GAG GTG TAC AAG GAG CGT CTC TTT GGG AAG AAG TAC GTC TGG TTC CTC 672 Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val Trp Phe Leu 210 215 220 ATT GGG TGG TAT GCT GAC AAT TGG TTC AAG ATC TAC GAC CCT TCT ATC 720 He Gly Trp Tyr Ala Asp Asn Trp Phe Lys He Tyr Asp Pro Ser He 225 230 235 240 AAC TGC ACA GTG GAT GAG ATG ACT GAG GCG GTG GAG GGC CAC ATC ACA 768 Asn Cys Thr Val Asp Glu Met Thr Glu Ala Val Glu Gly His He Thr 245 250 255 ACT GAG ATT GTC ATG CTG AAT CCT GCC AAT ACC CGC AGC ATT TCC AAC 816 Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser He Ser Asn 260 265 270 ATG ACA TCC CAG GAA TTT GTG GAG AAA CTA ACC AAG CGA CTG AAA AGA 864 Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg Leu Lys Arg 275 280 285 CAC CCT GAG GAG ACA GGA GGC TTC CAG GAG GCA CCG CTG GCC TAT GAT 912 His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu Ala Tyr Asp 290 295 300 GCC ATC TGG GCC TTG GCA CTG GCC CTG AAC AAG ACA TCT GGA GGA GGC 960 Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser Gly Gly Gly 305 310 315 320 GGC CGT TCT GGT GTG CGC CTG GAG GAC TTC AAC TAC AAC AAC CAG ACC 1008 Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn Asn Gin Thr 325 330 335 ATT ACC GAC CAA ATC TAC CGG GCA ATG AAC TCT TCG TCC TTT GAG GGT 1056 He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser Phe Glu Gly 340 345 350 GTC TCT GGC CAT GTG GTG TTT GAT GCC AGC GGC TCT CGG ATG GCA TGG 1104 Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg Met Ala Trp 355 360 365 ACG CTT ATC GAG CAG CTT CAG GGT GGC AGC TAC AAG AAG ATT GGC TAC 1152 Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys He Gly Tyr 370 375 380 TAT GAC AGC ACC AAG GAT GAT CTT TCC TGG TCC AAA ACA GAT AAA TGG 1200 Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr Asp Lys Trp 385 390 395 400 ATT GGA GGG TCC CCC CCA GCT GAC CAG ACC CTG GTC ATC AAG ACA TTC 1248 He Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He Lys Thr Phe 405 410 415 CGC TTC CTG TCA CAG AAA CTC TTT ATC TCC GTC TCA GTT CTC TCC AGC 1296 Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val Leu Ser Ser 420 425 430 CTG GGC ATT GTC CTA GCT GTT GTC TGT CTG TCC TTT AAC ATC TAC AAC 1344 Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn He Tyr Asn 435 440 445 TCA CAT GTC CGT TAT ATC CAG AAC TCA CAG CCC AAC CTG AAC AAC CTG 1392 Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu Asn Asn Leu 450 455 460 ACT GCT GTG GGC TGC TCA CTG GCT TTA GCT GCT GTC TTC CCC CTG GGG 1440 Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe Pro Leu Gly 465 470 475 480 CTC GAT GGT TAC CAC ATT GGG AGG AAC CAG TTT CCT TTC GTC TGC CAG 1488 Leu Asp Gly Tyr His He Gly Arg Asn Gin Phe Pro Phe Val Cys Gin 485 490 495 GCC CGC CTC TGG CTC CTG GGC CTG GGC TTT AGT CTG GGC TAC GGT TCC 1536 Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly Tyr Gly Ser 500 505 510 ATG TTC ACC AAG ATT TGG TGG GTC CAC ACG GTC TTC ACA AAG AAG GAA 1584 Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr Lys Lys Glu 515 520 525 GAA AAG AAG GAG TGG AGG AAG ACT CTG GAA CCC TGG AAG CTG TAT GCC 1632 Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys Leu Tyr Ala 530 535 540 ACA GTG GGC CTG CTG GTG GGC ATG GAT GTC CTC ACT CTC GCC ATC TGG 1680 Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu Ala He Trp 545 550 555 560 CAG ATC GTG GAC CCT CTG CAC CGG ACC ATT GAG ACA TTT GCC AAG GAG 1728 Gin He Val Asp Pro Leu His Arg Thr He Glu Thr Phe Ala Lys Glu 565 570 575 GAA CCT AAG GAA GAT ATT GAC GTC TCT ATT CTG CCC CAG CTG GAG CAT 1776 Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin Leu Glu His 580 585 590 TGC AGC TCC AGG AAG ATG AAT ACA TGG CTT GGC ATT TTC TAT GGT TAC 1824 Cys Ser Ser Arg Lys Met Asn Thr Trp Leu Gly He Phe Tyr Gly Tyr 595 600 605 AAG GGG CTG CTG CTG CTG CTG GGA ATC TTC CTT GCT TAT GAG ACC AAG 1872 Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr Glu Thr Lys 610 615 620 AGT GTG TCC ACT GAG AAG ATC AAT GAT CAC CGG GCT GTG GGC ATG GCT 1920 Ser Val Ser Thr Glu Lys He Asn Asp His Arg Ala Val Gly Met Ala 625 630 635 640 ATC TAC AAT GTG GCA GTC CTG TGC CTC ATC ACT GCT CCT GTC ACC ATG 1968 He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro Val Thr Met 645 650 655 ATT CTG TCC AGC CAG CAG GAT GCA GCC TTT GCC TTT GCC TCT CTT GCC 2016 He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala Ser Leu Ala 660 665 670 ATA GTT TTC TCC TCC TAT ATC ACT CTT GTT GTG CTC TTT GTG CCC AAG 2064 He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe Val Pro Lys 675 680 685 ATG CGC AGG CTG ATC ACC CGA GGG GAA TGG CAG TCG GAG GCG CAG GAC 2112 Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu Ala Gin Asp 690 695 700 ACC ATG AAG ACA GGG TCA TCG ACC AAC AAC AAC GAG GAG GAG AAG TCC 2160 Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu Glu Lys Ser 705 710 715 720 CGG CTG TTG GAG AAG GAG AAC CGT GAA CTG GAA AAG ATC ATT GCT GAG 2208 Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He He Ala Glu 725 730 735 AAA GAG GAG CGT GTC TCT GAA CTG CGC CAT CAA CTC CAG TCT CGG CAG 2256 Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin Ser Arg Gin 740 745 750 CAG CTC CGC TCC CGG CGC CAC CCA CCG ACA CCC CCA GAA CCC TCT GGG 2304 Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Glu Pro Ser Gly 755 760 765 GGC CTG CCC AGG GGA CCC CCT GAG CCC CCC GAC CGG CTT AGC TGT GAT 2352 Gly Leu Pro Arg Gly Pro Pro Glu Pro Pro Asp Arg Leu Ser Cys Asp 770 775 780 GGG AGT CGA GTG CAT TTG CTT TAT AAG TGAGGGTAGG GTGAGGGAGG 2399 Gly Ser Arg Val His Leu Leu Tyr Lys 785 790 ACAGGCCAGT AGGGGGAGGG AAAGGGAGAG GGGAAGGGCA GGGGACTCAG GAAGCAGGGG 2459 GTCCCCATCC CCAGCTGGGA AGAACATGCT ATCCAATCTC ATCTCTTGTA AATACATGTC 2519 CCCCTGTGAG TTCTGGGCTG ATTTGGGTCT CTCATACCTC TGGGAAACAG ACCTTTTTCT 2579 CTCTTACTGC TTCATGTAAT TTTGGAATTC CACCACACTG G 2620 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 793 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear .. (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly Trp Pro Gly 1 5 10 15 Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu Asp Val Asn 20 25 30 Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu He His His 35 40 45 Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu Tyr Glu Leu 50 55 60 Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly Cys Ser Ser 65 70 75 80 Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn Leu He Val 85 90 95 Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg Gin Arg Phe 100 105 110 Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His Asn Pro Thr 115 120 125 Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He Ala Thr He 130 135 140 Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp Leu Glu Glu 145 150 155 160 Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin Ser Phe Phe 165 170 175 Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin Asp Ala Arg 180 185 190 He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys Val Phe Cys 195 200 205 Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val Trp Phe Leu 210 215 220 He Gly Trp Tyr Ala Asp Asn Trp Phe Lys He Tyr Asp Pro Ser He 225 230 235 240 Asn Cys Thr Val Asp Glu Met Thr Glu Ala Val Glu Gly His He Thr 245 250 255 Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser He Ser Asn 260 265 270 Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg Leu Lys Arg 275 280 285 His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu Ala Tyr Asp 290 295 300 Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser Gly Gly Gly 305 310 315 320 Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn Asn Gin Thr 325 330 335 He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser Phe Glu Gly 340 345 350 Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg Met Ala Trp 355 360 365 Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys He Gly Tyr 370 375 380 Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr Asp Lys Trp 385 390 395 400 Ile Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He Lys Thr Phe 405 410 415 Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val Leu Ser Ser 420 425 430 Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn He Tyr Asn 435 440 445 Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu Asn Asn Leu 450 455 460 Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe Pro Leu Gly 465 470 ' 475 480 Leu Asp Gly Tyr His He Gly Arg Asn Gin Phe Pro Phe Val Cys Gin 485 490 495 Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly Tyr Gly Ser 500 505 510 Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr Lys Lys Glu 515 520 525 Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys Leu Tyr Ala 530 535 540 Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu Ala He Trp 545 550 555 560 Gin He Val Asp Pro Leu His Arg Thr He Glu Thr Phe Ala Lys Glu 565 570 575 Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin Leu Glu His 580 585 590 Cys Ser Ser Arg Lys Met Asn Thr Trp Leu Gly He Phe Tyr Gly Tyr 595 600 605 Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr Glu Thr Lys 610 615 620 Ser Val Ser Thr Glu Lys He Asn Asp His Arg Ala Val Gly Met Ala 625 630 635 640 He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro Val Thr Met 645 650 655 He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala Ser Leu Ala 660 665 670 He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe Val Pro Lys 675 680 685 Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu Ala Gin Asp 690 695 700 Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu Glu Lys Ser 705 710 715 720 Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He He Ala Glu 725 730 735 Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin Ser Arg Gin 740 745 750 Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Glu Pro Ser Gly 755 760 765 Gly Leu Pro Arg Gly Pro Pro Glu Pro Pro Asp Arg Leu Ser Cys Asp 770 775 780 Gly Ser Arg Val His Leu Leu Tyr Lys 785 790 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2837 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA to mRNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Rattus norvegicus (vii) IMMEDIATE SOURCE: (B) CLONE: GABABRlb rat (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION:228..2759 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION:228..2759 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: AACGGCCGCC AGTGTGCTGG AAAGGGAGAG TCCGCGGTGG CGGGAGCGAA CGTCTCCTGG 60 CCCTAGGAAG CCCACGTCTC TGCCTTCCCC GGGCTCTGGC CCCTCCTCCC CAATGAGACC 120 GGGGATGGAG ACACCTCCCC GACGCCCTCC CAGAAGCCTT CCCCAGAAGA AGTGTCCCCC 180 CTGAGCTGCC CCCCACCCCA AGGAGGCCGC CCCCGCCCCC CCTCGCC ATG GGC CCG 236 Met Gly Pro 1 GGG GGA CCC TGT ACC CCA GTG GGG TGG CCG CTG CCT CTT CTG CTG GTG 284 Gly Gly Pro Cys Thr Pro Val Gly Trp Pro Leu Pro Leu Leu Leu Val 5 10 15 ATG GCG GCT GGG GTG GCT CCG GTG TGG GCC TCT CAC TCC CCT CAT CTC 332 Met Ala Ala Gly Val Ala Pro Val Trp Ala Ser His Ser Pro His Leu 20 25 30 35 CCG CGG CCT CAC CCG AGG GTC CCC CCG CAC CCC TCC TCA GAA CGG CGT 380 Pro Arg Pro His Pro Arg Val Pro Pro His Pro Ser Ser Glu Arg Arg 40 45 50 GCA GTA TAC ATC GGG GCG CTG TTT CCC ATG AGC GGG GGC TGG CCG GGG 428 Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly Trp Pro Gly 55 60 65 GGC CAG GCC TGC CAG CCC GCG GTG GAG ATG GCG CTG GAG GAC GTT AAC 476 Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu Asp Val Asn 70 75 80 AGC CGC AGA GAC ATC CTG CCG GAC TAC GAG CTC AAG CTT ATC CAC CAC 524 Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu He His His 85 90 95 GAe AGC AAG TGT GAC CCA GGG CAA GCC ACC AAG TAC TTG TAC GAA CTA 572 Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu Tyr Glu Leu 100 105 110 115 CTC TAC AAT GAC CCC ATC AAG ATC ATT CTC ATG CCT GGC TGT AGT TCT 620 Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly Cys Ser Ser 120 125 130 GTC TCC ACA CTT GTA GCT GAG GCT GCC CGG ATG TGG AAC CTT ATT GTG 668 Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn Leu He Val 135 140 145 CTC TCA TAT GGC TCC AGT TCA CCA GCC TTG TCA AAC CGA CAG CGG TTT 716 Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg Gin Arg Phe 150 155 160 CCC ACG TTC TTC CGG ACG CAT CCA TCC GCC ACA CTC CAC AAT CCC ACC 764 Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His Asn Pro Thr 165 170 175 CGG GTG AAA CTC TTC GAA AAG TGG GGC TGG AAG AAG ATC GCT ACC ATC 812 Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He Ala Thr He 180 185 190 195 CAA CAG ACC ACC GAG GTC TTC ACC TCA ACG CTG GAT GAC CTG GAG GAG 860 Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp Leu Glu Glu 200 205 210 CGA GTG AAA GAG GCT GGG ATC GAG ATC ACT TTC CGA CAG AGT TTC TTC 908 Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin Ser Phe Phe 215 220 225 TCG GAT CCA GCT GTG CCT GTT AAA AAC CTG AAG CGT CAA GAT GCT CGA 956 Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin Asp Ala Arg 230 235 240 ATC ATC GTG GGA CTT TTC TAT GAG ACG GAA GCC CGG AAA GTT TTT TGT 1004 He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys Val Phe Cys 245 250 255 GAG GTC TAT AAG GAA AGG CTC TTT GGG AAG AAG TAC GTC TGG TTC CTC 1052 Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val Trp Phe Leu 260 265 270 275 ATC GGG TGG TAT GCT GAC AAC TGG TTC AAG ACC TAT GAC CCG TCA ATC 1100 He Gly Trp Tyr Ala Asp Asn Trp Phe Lys Thr Tyr Asp Pro Ser He 280 285 290 AAT TGT ACA GTG GAA GAA ATG ACC GAG GCG GTG GAG GGC CAC ATC ACC 1148 Asn Cys Thr Val Glu Glu Met Thr Glu Ala Val Glu Gly His He Thr 295 300 305 ACG GAG ATT GTC ATG CTG AAC CCT GCC AAC ACC CGA AGC ATT TCC AAC 1196 Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser He Ser Asn 310 315 320 ATG ACG TCA CAG GAA TTT GTG GAG AAA CTA ACC AAG CGG CTG AAA AGA 1244 Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg Leu Lys Arg 325 330 335 CAC CCC GAG GAG ACT GGA GGC TTC CAG GAG GCA CCA CTG GCC TAT GAT 1292 His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu Ala Tyr Asp 340 345 350 355 GCT ATC TGG GCC TTG GCT TTG GCC TTG AAC AAG ACG TCT GGA GGA GGT 1340 Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser Gly Gly Gly 360 365 370 GGT CGT TCC GGC GTG CGC CTG GAG GAC TTT AAC TAC AAC AAC CAG ACC 1388 Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn Asn Gin Thr 375 380 385 ATT ACA GAC CAG ATC TAC CGG GCC ATG AAC TCC TCC TCC TTT GAG GGC 1436 He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser Phe Glu Gly 390 395 400 GTT TCT GGC CAT GTG GTC TTT GAT GCC AGC GGC TCC CGG ATG GCA TGG 1484 Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg Met Ala Trp 405 410 415 ACA CTT ATC GAG CAG CTA CAG GGC GGC AGC TAC AAG AAG ATC GGC TAC 1532 Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys He Gly Tyr 420 425 430 435 TAC GAC AGC ACC AAG GAT GAT CTT TCC TGG TCC AAA ACG GAC AAG TGG 1580 Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr Asp Lys Trp 440 445 450 ATT GGA GGG TCT CCC CCA GCT GAC CAG ACC TTG GTC ATC AAG ACA TTC 1628 He Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He Lys Thr Phe 455 460 465 CGT TTC CTG TCT CAG AAA CTC TTT ATC TCC GTC TCA GTT CTC TCC AGC 1676 Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val Leu Ser Ser 470 475 480 CTG GGC ATT GTT CTT GCT GTT GTC TGT CTG TCC TTT AAC ATC TAC AAC 1724 Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn He Tyr Asn 485 490 495 TCC CAC GTT CGT TAT ATC CAG AAC TCC CAG CCC AAC CTG AAC AAT CTG 1772 Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu Asn Asn Leu 500 505 510 515 ACT GCT GTG GGC TGC TCA CTG GCA CTG GCT GCT GTC TTC CCT CTC GGG 1820 Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe Pro Leu Gly 520 525 530 CTG GAT GGT TAC CAC ATA GGG AGA AGC CAG TTC CCG TTT GTC TGC CAG 1868 Leu Asp Gly Tyr His He Gly Arg Ser Gin Phe Pro Phe Val Cys Gin 535 540 545 GCC CGC CTT TGG CTC TTG GGC TTG GGC TTT AGT CTG GGC TAT GGC TCT 1916 Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly Tyr Gly Ser 550 555 560 ATG TTC ACC AAG ATC TGG TGG GTC CAC ACA GTC TTC ACG AAG AAG GAG 1964 Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr Lys Lys Glu 565 570 575 GAG AAG AAG GAG TGG AGG AAG ACC CTA GAG CCC TGG AAA CTC TAT GCC 2012 Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys Leu Tyr Ala 580 585 590 595 ACT GTG GGC CTG CTG GTG GGC ATG GAT GTC CTG ACT CTT GCC ATC TGG 2060 Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu Ala He Trp 600 605 610 CAG ATT GTG GAC CCC TTG CAC CGA ACC ATT GAG ACT TTT GCC AAG GAG 2108 Gin He Val Asp Pro Leu His Arg Thr He Glu Thr Phe Ala Lys Glu 615 620 625 GAA CCA AAG GAA GAC ATC GAT GTC TCC ATT CTG CCC CAG TTG GAG CAC 2156 Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin Leu Glu His 630 635 640 TGC AGC TCC AAG AAG ATG AAT ACG TGG CTT GGC ATT TTC TAT GGT TAC 2204 Cys Ser Ser Lys Lys Met Asn Thr Trp Leu Gly He Phe Tyr Gly Tyr 645 650 655 AAG GGG CTG CTG CTG CTG CTG GGA ATC TTT CTT GCT TAC GAA ACC AAG 2252 Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr Glu Thr Lys 660 665 670 675 AGC GTG TCC ACT GAA AAG ATC AAT GAC CAC AGG GCC GTG GGC ATG GCT 2300 Ser Val Ser Thr Glu Lys He Asn Asp His Arg Ala Val Gly Met Ala 680 685 690 ATC TAC AAT GTC GCG GTC CTG TGT CTC ATC ACT GCT CCT GTG ACC ATG 2348 He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro Val Thr Met 695 700 705 ATC CTT TCC AGT CAG CAG GAC GCA GCC TTT GCC TTT GCC TCT CTG GCC 2396 He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala Ser Leu Ala 710 715 720 ATC GTG TTC TCT TCC TAC ATC ACT CTG GTT GTG CTC TTT GTG CCC AAG 2444 He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe Val Pro Lys 725 730 735 ATG CGC AGG CTG ATC ACC CGA GGG GAA TGG CAG TCT GAA ACG CAG GAC 2492 Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu Thr Gin Asp 740 745 750 755 ACC ATG AAA ACA GGA TCA TCC ACC AAC AAC AAC GAG GAA GAG AAG TCC 2540 Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu Glu Lys Ser 760 765 770 CGA CTG TTG GAG AAG GAA AAC CGA GAA CTG GAA AAG ATC ATC GCT GAG 2588 Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He He Ala Glu 775 780 785 AAA GAG GAG CGC GTC TCT GAA CTG CGC CAT CAG CTC CAG TCT CGG CAG 2636 Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin Ser Arg Gin 790 795 800 CAA CTC CGC TCA CGG CGC CAC CCC CCA ACA CCC CCA GAT CCC TCT GGG 2684 Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Asp Pro Ser Gly 805 810 815 GGC CTT CCC AGG GGA CCC TCT GAG CCC CCT GAC CGG CTT AGC TGT GAT 2732 Gly Leu Pro Arg Gly Pro Ser Glu Pro Pro Asp Arg Leu Ser Cys Asp 820 825 830 835 GGG AGT CGA GTA CAT TTG CTT TAC AAG TGAGGGGGCA TGGAGAAGGA 2779 Gly Ser Arg Val His Leu Leu Tyr Lys 840 TCTCCCTGAA TCTCAATAAA GCAGTGAACA GTAAACTTTC CAGCACACTG GCGGCCGC 2837 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 844 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Met Gly Pro Gly Gly Pro Cys Thr Pro Val Gly Trp Pro Leu Pro Leu 1 5 10 15 Leu Leu Val Met Ala Ala Gly Val Ala Pro Val Trp Ala Ser His Ser 20 25 30 Pro His Leu Pro Arg Pro His Pro Arg Val Pro Pro His Pro Ser Ser 35 40 45 Glu Arg Arg Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly 50 55 60 Trp Pro Gly Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu 65 70 75 80 Asp Val Asn Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu 85 90 95 He His His Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu 100 105 110 Tyr Glu Leu Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly 115 120 125 Cys Ser Ser Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn 130 135 140 Leu He Val Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg 145 150 155 160 Gin Arg Phe Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His 165 170 175 Asn Pro Thr Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He 180 185 190 Ala Thr He Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp 195 200 205 Leu Glu Glu Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin 210 215 220 Ser Phe Phe Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin 225 230 235 240 Asp Ala Arg He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys 245 250 255 Val Phe Cys Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val 260 265 270 Trp Phe Leu He Gly Trp Tyr Ala Asp Asn Trp Phe Lys Thr Tyr Asp 275 280 285 Pro Ser He Asn Cys Thr Val Glu Glu Met Thr Glu Ala Val Glu Gly 290 295 300 His He Thr Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser 305 310 315 320 He Ser Asn Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg 325 330 335 Leu Lys Arg His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu 340 345 350 Ala Tyr Asp Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser 355 360 365 Gly Gly Gly Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn 370 375 380 Asn Gin Thr He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser 385 390 395 400 Phe Glu Gly Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg 405 410 415 Met Ala Trp Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys 420 425 430 He Gly Tyr Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr 435 440 445 Asp Lys Trp He Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He 450 455 460 Lys Thr Phe Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val 465 470 475 480 Leu Ser Ser Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn 485 490 495 He Tyr Asn Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu 500 505 510 Asn Asn Leu Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe 515 520 525 Pro Leu Gly Leu Asp Gly Tyr His He Gly Arg Ser Gin Phe Pro Phe 530 535 540 Val Cys Gin Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly 545 550 ' 555 560 Tyr Gly Ser Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr 565 570 575 Lys Lys Glu Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys 580 585 590 Leu Tyr Ala Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu 595 600 605 Ala He Trp Gin He Val Asp Pro Leu His Arg Thr He Glu Thr Phe 610 615 620 Ala Lys Glu Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin 625 630 635 640 Leu Glu His Cys Ser Ser Lys Lys Met Asn Thr Trp Leu Gly He Phe 645 650 655 Tyr Gly Tyr Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr 660 665 670 Glu Thr Lys Ser Val. Ser Thr Glu Lys He Asn Asp His Arg Ala Val 675 680 685 Gly Met Ala He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro 690 695 700 Val Thr Met He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala 705 710 715 720 Ser Leu Ala He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe 725 730 735 Val Pro Lys Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu 740 745 750 Thr Gin Asp Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu 755 760 765 Glu Lys Ser Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He 770 775 780 He Ala Glu Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin 785 790 795 800 Ser Arg Gin Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Asp 805 810 815 Pro Ser Gly Gly Leu Pro Arg Gly Pro Ser Glu Pro Pro Asp Arg Leu 820 825 830 Ser Cys Asp Gly Ser Arg Val His Leu Leu Tyr Lys 835 840 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2924 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA to mRNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (vii) IMMEDIATE SOURCE: (B) CLONE: GABABRlb human (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION:169..2700 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION:169..2700 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: GGCCGTAGGA AGCCAACCTT CCCTGCTTCT CCGGGGCCCT CGCCCCCTCC TCCCCACAAA 60 ATCAGGGATG GAGGCGCCTC CCCGGCACCC TCTTAGCAGC CCTCCCCAGG AAAAGTGTCC 120 CCCCTGAGCT CCTAACGCTC CCCAACAGCT ACCCCTGCCC CCCACGCC ATG GGG CCC 177 Met Gly Pro 1 GGG GCC CCT TTT GCC CGG GTG GGG TGG CCA CTG CCG CTT CTG GTT GTG 225 Gly Ala Pro Phe Ala Arg Val Gly Trp Pro Leu Pro Leu Leu Val Val 5 10 15 ATG GCG GCA GGG GTG GCT CCG GTG TGG GCC TCC CAC TCC CCC CAT CTC 273 Met Ala Ala Gly Val Ala Pro Val Trp Ala Ser His Ser Pro His Leu 20 25 30 35 CCG CGG CCT CAC TCG CGG GTC CCC CCG CAC CCC TCC TCA GAA CGG CGC 321 Pro Arg Pro His Ser Arg Val Pro Pro His Pro Ser Ser Glu Arg Arg 40 45 50 GCA GTG TAC ATC GGG GCA CTG TTT CCC ATG AGC GGG GGC TGG CCA GGG 369 Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly Trp Pro Gly 55 60 65 GGC CAG GCC TGC CAG CCC GCG GTG GAG ATG GCG CTG GAG GAC GTG AAT 417 Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu Asp Val Asn 70 75 80 AGC CGC AGG GAC ATC CTG CCG GAC TAT GAG CTC AAG CTC ATC CAC CAC 465 Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu He His His 85 90 95 GAC AGC AAG TGT GAT CCA GGC CAA GCC ACC AAG TAC CTA TAT GAG CTG 513 Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu Tyr Glu Leu 100 105 110 115 CTC TAC AAC GAC CCT ATC AAG ATC ATC CTT ATG CCT GGC TGC AGC TCT 561 Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly Cys Ser Ser 120 125 130 GTC TCC ACG CTG GTG GCT GAG GCT GCT AGG ATG TGG AAC CTC ATT GTG 609 Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn Leu He Val 135 140 145 CTT TCC TAT GGC TCC AGC TCA CCA GCC CTG TCA AAC CGG CAG CGT TTC 657 Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg Gin Arg Phe 150 155 160 CCC ACT TTC TTC CGA ACG CAC CCA TCA GCC ACA CTC CAC AAC CCT ACC 705 Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His Asn Pro Thr 165 170 175 CGC GTG AAA CTC TTT GAA AAG TGG GGC TGG AAG AAG ATT GCT ACC ATC 753 Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He Ala Thr He 180 185 190 195 CAG CAG ACC ACT GAG GTC TTC ACT TCG ACT CTG GAC GAC CTG GAG GAA 801 Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp Leu Glu Glu 200 205 210 CGA GTG AAG GAG GCT GGA ATT GAG ATT ACT TTC CGC CAG AGT TTC TTC 849 Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin Ser Phe Phe 215 220 225 TCA GAT CCA GCT GTG CCC GTC AAA AAC CTG AAG CGC CAG GAT GCC CGA 897 Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin Asp Ala Arg 230 235 240 ATC ATC GTG GGA CTT TTC TAT GAG ACT GAA GCC CGG AAA GTT TTT TGT 945 He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys Val Phe Cys 245 250 255 GAG GTG TAC AAG GAG CGT CTC TTT GGG AAG AAG TAC GTC TGG TTC CTC 993 Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val Trp Phe Leu 260 265 270 275 ATT GGG TGG TAT GCT GAC AAT TGG TTC AAG ATC TAC GAC CCT TCT ATC 1041 He Gly Trp Tyr Ala Asp Asn Trp Phe Lys He Tyr Asp Pro Ser He 280 285 290 AAC TGC ACA GTG GAT GAG ATG ACT GAG GCG GTG GAG GGC CAC ATC ACA 1089 Asn Cys Thr Val Asp Glu Met Thr Glu Ala Val Glu Gly His He Thr 295 300 305 ACT GAG ATT GTC ATG CTG AAT CCT GCC AAT ACC CGC AGC ATT TCC AAC 1137 Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser He Ser Asn 310 315 320 ATG ACA TCC CAG GAA TTT GTG GAG AAA CTA ACC AAG CGA CTG AAA AGA 1185 Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg Leu Lys Arg 325 330 335 CAC CCT GAG GAG ACA GGA GGC TTC CAG GAG GCA CCG CTG GCC TAT GAT 1233 His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu Ala Tyr Asp 340 345 350 355 GCC ATC TGG GCC TTG GCA CTG GCC CTG AAC AAG ACA TCT GGA GGA GGC 1281 Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser Gly Gly Gly 360 365 370 GGC CGT TCT GGT GTG CGC CTG GAG GAC TTC AAC TAC AAC AAC CAG ACC 1329 Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn Asn Gin Thr 375 380 385 ATT ACC GAC CAA ATC TAC CGG GCA ATG AAC TCT TCG TCC TTT GAG GGT 1377 He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser Phe Glu Gly 390 395 400 GTC TCT GGC CAT GTG GTG TTT GAT GCC AGC GGC TCT CGG ATG GCA TGG 1425 Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg Met Ala Trp 405 410 415 ACG CTT ATC GAG CAG CTT CAG GGT GGC AGC TAC AAG AAG ATT GGC TAC 1473 Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys He Gly Tyr 420 425 430 435 TAT GAC AGC ACC AAG GAT GAT CTT TCC TGG TCC AAA ACA GAT AAA TGG 1521 Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr Asp Lys Trp 440 445 450 ATT GGA GGG TCC CCC CCA GCT GAC CAG ACC CTG GTC ATC AAG ACA TTC 1569 He Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He Lys Thr Phe 455 460 465 CGC TTC CTG TCA CAG AAA CTC TTT ATC TCC GTC TCA GTT CTC TCC AGC 1617 Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val Leu Ser Ser 470 475 480 CTG GGC ATT GTC CTA GCT GTT GTC TGT CTG TCC TTT AAC ATC TAC AAC 1665 Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn He Tyr Asn 485 490 495 TCA CAT GTC CGT TAT ATC CAG AAC TCA CAG CCC AAC CTG AAC AAC CTG 1713 Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu Asn Asn Leu 500 505 510 515 ACT GCT GTG GGC TGC TCA CTG GCT TTA GCT GCT GTC TTC CCC CTG GGG 1761 Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe Pro Leu Gly 520 525 530 CTC GAT GGT TAC CAC ATT GGG AGG AAC CAG TTT CCT TTC GTC TGC CAG 1809 Leu Asp Gly Tyr His He Gly Arg Asn Gin Phe Pro Phe Val Cys Gin 535 540 545 GCC CGC CTC TGG CTC CTG GGC CTG GGC TTT AGT CTG GGC TAC GGT TCC 1857 Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly Tyr Gly Ser 550 555 560 ATG TTC ACC AAG ATT TGG TGG GTC CAC ACG GTC TTC ACA AAG AAG GAA 1905 Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr Lys Lys Glu 565 570 575 GAA AAG AAG GAG TGG AGG AAG ACT CTG GAA CCC TGG AAG CTG TAT GCC 1953 Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys Leu Tyr Ala 580 585 590 595 ACA GTG GGC CTG CTG GTG GGC ATG GAT GTC CTC ACT CTC GCC ATC TGG 2001 Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu Ala He Trp 600 605 610 CAG ATC GTG GAC CCT CTG CAC CGG ACC ATT GAG ACA TTT GCC AAG GAG 2049 Gin He Val Asp Pro Leu His Arg Thr lie Glu Thr Phe Ala Lys Glu 615 620 625 GAA CCT AAG GAA GAT ATT GAC GTC TCT ATT CTG CCC CAG CTG GAG CAT 2097 Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin Leu Glu His 630 635 640 TGC AGC TCC AGG AAG ATG AAT ACA TGG CTT GGC ATT TTC TAT GGT TAC 2145 Cys Ser Ser Arg Lys Met Asn Thr Trp Leu Gly He Phe Tyr Gly Tyr 645 650 655 AAG GGG CTG CTG CTG CTG CTG GGA ATC TTC CTT GCT TAT GAG ACC AAG 2193 Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr Glu Thr Lys 660 665 670 675 AGT GTG TCC ACT GAG AAG ATC AAT GAT CAC CGG GCT GTG GGC ATG GCT 2241 Ser Val Ser Thr Glu Lys He Asn Asp His Arg Ala Val Gly Met Ala 680 685 690 ATC TAC AAT GTG GCA GTC CTG TGC CTC ATC ACT GCT CCT GTC ACC ATG 2289 He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro Val Thr Met 695 700 705 ATT CTG TCC AGC CAG CAG GAT GCA GCC TTT GCC TTT GCC TCT CTT GCC 2337 He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala Ser Leu Ala 710 715 720 ATA GTT TTC TCC TCC TAT ATC ACT CTT GTT GTG CTC TTT GTG CCC AAG 2385 He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe Val Pro Lys 725 730 735 ATG CGC AGG CTG ATC ACC CGA GGG GAA TGG CAG TCG GAG GCG CAG GAC 2433 Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu Ala Gin Asp 740 745 750 755 ACC ATG AAG ACA GGG TCA TCG ACC AAC AAC AAC GAG GAG GAG AAG TCC 2481 Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu Glu Lys Ser 760 765 770 CGG CTG TTG GAG AAG GAG AAC CGT GAA CTG GAA AAG ATC ATT GCT GAG 2529 Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He He Ala Glu 775 780 785 AAA GAG GAG CGT GTC TCT GAA CTG CGC CAT CAA CTC CAG TCT CGG CAG 2577 Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin Ser Arg Gin 790 795 800 CAG CTC CGC TCC CGG CGC CAC CCA CCG ACA CCC CCA GAA CCC TCT GGG 2625 Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Glu Pro Ser Gly 805 810 815 GGC CTG CCC AGG GGA CCC CCT GAG CCC CCC GAC CGG CTT AGC TGT GAT 2673 Gly Leu Pro Arg Gly Pro Pro Glu Pro Pro Asp Arg Leu Ser Cys Asp 820 825 830 835 GGG AGT CGA GTG CAT TTG CTT TAT AAG TGAGGGTAGG GTGAGGGAGG 2720 Gly Ser Arg Val His Leu Leu Tyr Lys 840 ACAGGCCAGT AGGGGGAGGG AAAGGGAGAG GGGAAGGGCA GGGGACTCAG GAAGCAGGGG 2780 GTCCCCATCC CCAGCTGGGA AGAACATGCT ATCCAATCTC ATCTCTTGTA AATACATGTC 2840 CCCCTGTGAG TTCTGGGCTG ATTTGGGTCT CTCATACCTC TGGGAAACAG ACCTTTTTCT 2900 CTCTTACTGC TTCATGTAAT TTTG 2924 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 844 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Met Gly Pro Gly Ala Pro Phe Ala Arg Val Gly Trp Pro Leu Pro Leu 1 5 10 15 Leu Val Val Met Ala Ala Gly Val Ala Pro Val Trp Ala Ser His Ser 20 25 30 Pro His Leu Pro Arg Pro His Ser Arg Val Pro Pro His Pro Ser Ser 35 40 45 Glu Arg Arg Ala Val Tyr He Gly Ala Leu Phe Pro Met Ser Gly Gly 50 55 60 Trp Pro Gly Gly Gin Ala Cys Gin Pro Ala Val Glu Met Ala Leu Glu 65 70 75 80 Asp Val Asn Ser Arg Arg Asp He Leu Pro Asp Tyr Glu Leu Lys Leu 85 90 95 Ile His His Asp Ser Lys Cys Asp Pro Gly Gin Ala Thr Lys Tyr Leu 100 105 110 Tyr Glu Leu Leu Tyr Asn Asp Pro He Lys He He Leu Met Pro Gly 115 120 125 Cys Ser Ser Val Ser Thr Leu Val Ala Glu Ala Ala Arg Met Trp Asn 130 135 140 Leu He Val Leu Ser Tyr Gly Ser Ser Ser Pro Ala Leu Ser Asn Arg 145 150 155 160 Gin Arg Phe Pro Thr Phe Phe Arg Thr His Pro Ser Ala Thr Leu His 165 170 175 Asn Pro Thr Arg Val Lys Leu Phe Glu Lys Trp Gly Trp Lys Lys He 180 185 190 Ala Thr He Gin Gin Thr Thr Glu Val Phe Thr Ser Thr Leu Asp Asp 195 200 205 Leu Glu Glu Arg Val Lys Glu Ala Gly He Glu He Thr Phe Arg Gin 210 215 220 Ser Phe Phe Ser Asp Pro Ala Val Pro Val Lys Asn Leu Lys Arg Gin 225 230 235 240 Asp Ala Arg He He Val Gly Leu Phe Tyr Glu Thr Glu Ala Arg Lys 245 250 255 Val Phe Cys Glu Val Tyr Lys Glu Arg Leu Phe Gly Lys Lys Tyr Val 260 265 270 Trp Phe Leu He Gly Trp Tyr Ala Asp Asn Trp Phe Lys He Tyr Asp 275 280 285 Pro Ser He Asn Cys Thr Val Asp Glu Met Thr Glu Ala Val Glu Gly 290 295 300 His He Thr Thr Glu He Val Met Leu Asn Pro Ala Asn Thr Arg Ser 305 310 315 320 He Ser Asn Met Thr Ser Gin Glu Phe Val Glu Lys Leu Thr Lys Arg 325 330 335 Leu Lys Arg His Pro Glu Glu Thr Gly Gly Phe Gin Glu Ala Pro Leu 340 345 350 Ala Tyr Asp Ala He Trp Ala Leu Ala Leu Ala Leu Asn Lys Thr Ser 355 360 365 Gly Gly Gly Gly Arg Ser Gly Val Arg Leu Glu Asp Phe Asn Tyr Asn 370 375 380 Asn Gin Thr He Thr Asp Gin He Tyr Arg Ala Met Asn Ser Ser Ser 385 390 395 400 Phe Glu Gly Val Ser Gly His Val Val Phe Asp Ala Ser Gly Ser Arg 405 410 415 Met Ala Trp Thr Leu He Glu Gin Leu Gin Gly Gly Ser Tyr Lys Lys 420 425 430 He Gly Tyr Tyr Asp Ser Thr Lys Asp Asp Leu Ser Trp Ser Lys Thr 435 440 445 Asp Lys Trp He Gly Gly Ser Pro Pro Ala Asp Gin Thr Leu Val He 450 455 460 Lys Thr Phe Arg Phe Leu Ser Gin Lys Leu Phe He Ser Val Ser Val 465 470 475 480 Leu Ser Ser Leu Gly He Val Leu Ala Val Val Cys Leu Ser Phe Asn 485 490 495 He Tyr Asn Ser His Val Arg Tyr He Gin Asn Ser Gin Pro Asn Leu 500 505 510 Asn Asn Leu Thr Ala Val Gly Cys Ser Leu Ala Leu Ala Ala Val Phe 515 520 525 Pro Leu Gly Leu Asp Gly Tyr His He Gly Arg Asn Gin Phe Pro Phe 530 535 540 Val Cys Gin Ala Arg Leu Trp Leu Leu Gly Leu Gly Phe Ser Leu Gly 545 550 555 560 Tyr Gly Ser Met Phe Thr Lys He Trp Trp Val His Thr Val Phe Thr 565 570 575 Lys Lys Glu Glu Lys Lys Glu Trp Arg Lys Thr Leu Glu Pro Trp Lys 580 585 590 Leu Tyr Ala Thr Val Gly Leu Leu Val Gly Met Asp Val Leu Thr Leu 595 600 605 Ala He Trp Gin He Val Asp Pro Leu His Arg Thr He Glu Thr Phe 610 615 620 Ala Lys Glu Glu Pro Lys Glu Asp He Asp Val Ser He Leu Pro Gin 625 630 635 640 Leu Glu His Cys Ser Ser Arg Lys Met Asn Thr Trp Leu Gly He Phe 645 650 655 Tyr Gly Tyr Lys Gly Leu Leu Leu Leu Leu Gly He Phe Leu Ala Tyr 660 665 670 Glu Thr Lys Ser Val Ser Thr Glu Lys He Asn Asp His Arg Ala Val 675 680 685 Gly Met Ala He Tyr Asn Val Ala Val Leu Cys Leu He Thr Ala Pro 690 695 700 Val Thr Met He Leu Ser Ser Gin Gin Asp Ala Ala Phe Ala Phe Ala 705 710 715 720 Ser Leu Ala He Val Phe Ser Ser Tyr He Thr Leu Val Val Leu Phe 725 730 735 Val Pro Lys Met Arg Arg Leu He Thr Arg Gly Glu Trp Gin Ser Glu 740 745 750 Ala Gin Asp Thr Met Lys Thr Gly Ser Ser Thr Asn Asn Asn Glu Glu 755 760 765 Glu Lys Ser Arg Leu Leu Glu Lys Glu Asn Arg Glu Leu Glu Lys He 770 775 780 He Ala Glu Lys Glu Glu Arg Val Ser Glu Leu Arg His Gin Leu Gin 785 790 795 800 Ser Arg Gin Gin Leu Arg Ser Arg Arg His Pro Pro Thr Pro Pro Glu 805 810 815 Pro Ser Gly Gly Leu Pro Arg Gly Pro Pro Glu Pro Pro Asp Arg Leu 820 825 830 Ser Cys Asp Gly Ser Arg Val His Leu Leu Tyr Lys 835 840 INDICATIONS RELATING TO A DEPOSITED MICROORGANISM For International Bureau use only J J This sheet was received by the International Bureau on: Authorized officer INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rule I3bιs) A. The indications made below relate to the microorganism referred lo in the description B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet I I Name of depositary institution Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) Address of depositary institution (includin postal code and country) Mascheroder Weg IB D-38124 Braunschweig Germany Dale of deposit Accession Number 21 February 1997 (21.02.97) DSM 11421 C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet | ) We request the Expert Solution where available D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indications are not for all designated States) E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable) The indications listed below will be submitted to the International Bureau later (specify the general nature of the indications e g , "Accession Number of Deposit") For receiving Office use only For International Bureau use only This sheet was received with the international application j j This sheet was received by the International Bureau on" Authorized officer Authorized officer Form PCι7RO/134 (July 1992) INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rule \ 3bis) For receiving Office use only For International Bureau use only This sheet was received with the international application I j This sheet was received by the International Bureau on: Authorized officer Authorized officer Form PCT/RO/134 (July 1992)

Claims: What is claimed is: 1. A purified GABA B receptor or receptor protein. 2. A GABA B receptor or receptor protein according to claim 1 which is capable of specific binding to at least one of the selective GABA B receptor antagonists of Formulae I or II: [ 125 I]CGP62413 Ϊ 125 I]CGP71872 3. A GABA B receptor or receptor protein according to claim 1 which is encoded by any one of the nucleic acid sequences set forth in the group consisting of SEQ ID No. 1 , SEQ ID No. 3, SEQ ID No. 5 and SEQ ID No. 7, or by a nucleic acid clone selected from the group consisting of clones deposited at the DSMZ under accession numbers DSM 10689, DSM 11421 and DSM 11422. 4. A GABA B receptor or receptor protein according to claim 1 having substantial homology to any one of the amino acid sequences set forth in the group consisting of SEQ ID No. 2, SEQ ID No. 4, SEQ ID No. 6 and SEQ ID No. 8. 5. A GABAB receptor or receptor protein according to claim 1 which is a human GABA B receptor or receptor protein. 6. A GABA B receptor or receptor protein according to claim 5 having substantially the same amino acid sequence as set forth in SEQ ID No. 8. 7. An isolated nucleic acid encoding a GABA B receptor or receptor protein. 8. A method for identifying a nucleic acid encoding a GABA B receptor or receptor protein, comprising the steps of: preparing an expression library encoding cDNA molecules which potentially encode a GABA B receptor or receptor protein; screening the expression library with a specific ligand capable of binding to a GABA B receptor or receptor protein; and isolating the cDNA clone encoding a GABA B receptor or receptor protein. 9. A method for identifying a nucleic acid encoding a GABA B receptor or receptor protein, comprising the steps of: preparing a library encoding cDNA or genomic DNA molecules which potentially encode a GABA B receptor or receptor protein; screening the library by hybridisation with a nucleic acid probe which is capable of hybridising to any one of the nucleic acid sequences set forth in the group consisting of SEQ ID No. 1 , SEQ ID No. 3 , SEQ ID No. 5 and SEQ ID No. 7; and identifying the nucleic acid molecules which hybridise to the probe. 10. A method for screening compounds or mixtures of compounds which are potential modulators of GABA B receptor activity, comprising the steps of: preparing a test system comprising a recombinant GABA B receptor or receptor protein; exposing the test system to the compound or mixture of compounds; identifying the compound or mixture of compounds which causes modulation of GABA B receptor activity as measured by the test system. 1 1 . A method for screening compounds or mixtures of compounds which are potential modulators of GABA B receptor expression, comprising the steps of: providing an expression system comprising a test gene operably linked to control sequences normally associated with a gene encoding a GABA B receptor or receptor protein; identifying the compounds which cause a change in the level of expression of the test gene. 12. A nucleic acid complementary to the nucleic acid of claim 7. 13. A nucleic acid probe which is capable of hybridising to any one of the nucleic acid sequences set forth in the group consisting of SEQ ID No. 1 , SEQ ID No. 3 , SEQ ID No. 5 and SEQ ID No. 7, under conditions of low stringency. 14. A nucleic acid according to claim 13 which is an antisense nucleic acid. 15. A method according to claim 8 wherein the specific ligand is the compound of Formula I or the compound of Formula II. 16. A replicable nucleic acid vector comprising a coding sequence consisting of a nucleic acid according to claim 7 operably linked to suitable control sequences. 17. A host cell transformed with a vector according to claim 16. 18. An antibody specific for GABA B receptor or receptor protein. 19. A transgenic non-human mammal which has been modified to modulate the expression of GABA B receptor or receptor protein. 20. The selective GABA B receptor antagonist of Formula I. 21. The selective GABA B receptor antagonist of Formula II.

Inventors: BETTLER BERNHARD, BITTIGER HELMUT, FROESTL WOLFGANG, KAUPMANN KLEMENS, MICKEL STUART JOHN, BETTLER, BERNHARD, BITTIGER, HELMUT, FROESTL, WOLFGANG, KAUPMANN, KLEMENS, MICKEL, STUART, JOHN
Applicants: BETTLER BERNHARD, BITTIGER HELMUT, CIBA GEIGY AG, FROESTL WOLFGANG, KAUPMANN KLEMENS, MICKEL STUART JOHN, BETTLER, BERNHARD, BITTIGER, HELMUT, FROESTL, WOLFGANG, KAUPMANN, KLEMENS, MICKEL, STUART, JOHN, NOVARTIS AG
Application year: 1997
Main classification: C12N15
IPC codes: A01K67, A61K38, C07F9, C07K14, C07K16, C12N1, C12N5, C12N15, C12P21, C12Q1, G01N33