Patent Publication Number: US-2003224416-A1

Title: Schizophrenia related gene

Description:
TECHNICAL FIELD OF THE INVENTION  
       [0001] The present invention relates to the gene of the voltage-gated potassium channels Kv3. The present invention also relates to its use in the therapy and/or diagnosis of schizophrenia and to a method of screening for a compound which modulates the expression of the gene or the activity of the voltage-gated-potassium channels.  
       BACKGROUND OF THE INVENTION  
       [0002] Schizophrenia is a devastating mental illness that affects 1%,of the world population, the aetiology of which remains elusive. To date, there is a poor understanding of the genes involved. One of the goals of modern antipsychotic drug development is to produce a drug which is more effective in ameliorating the negative symptoms and cognitive deficits characteristic of schizophrenia than existing therapies. Although typical and a typical antipsychotic drugs, such as haloperidol and clozapine respectively, are effective in attenuating the positive symptoms, they are ineffective (haloperidol) or minimally effective (clozapine) against the negative symptoms and cognitive dysfunction associated with the disease (Goldberg, T. E. et al. British Journal of Psychiatry, 1993, 162; 43-48). The development of improved antipsychotic drugs that will have superior action against the negative symptoms and cognitive dysfunction has been severely hampered by the lack of knowledge of which genes are involved and/or associated with schizophrenia. Moreover little is known about the genes, or more specifically any alteration of expression or mutation of the genes in a patient suffering from schizophrenia.  
       [0003] The Shaw-related family of voltage-gated potassium channels (also known as Kv3 channels) are encoded by four genes (Kv3.1, Kv3.2, Kv3.3 and Kv3.4). The products of these genes have differential expression within the mammalian brain, with Kv3.1 and Kv3.3 channels being predominantly located within a subset of GABAergic interneurons within the brain, namely parvalbumin-containing interneurons (Weiser et al., The Journal of Neuroscience, March 1994, 14(3); 949-972). The function of Kv3.1 and Kv3.3 channels within these interneurons is to allow fast repolarisation of the cells and thus, contributes to the fast-firing phenotype of these neurons (Du et al. The Journal of Neuroscience, Jan. 15, 1996, 16(2); 506-518, Chow et al., The Journal of Neuroscience, Nov. 1, 1999, 19(21); 9332-9345; Erisir et al., The Journal of Neurophysiology, 1999, 82; 2476-2489). Kv3.2 expression is predominantly (90%) within thalamic relay neurons throughout the dorsal thalamus and also in parvalbumin-containing and other GABAergic (Marinotti) interneurons (Moreno et al., The Journal of Neuroscience, August, 1995,15(8); 5486-5501). Parvalbumin expression has been shown to be altered within the prefrontal cortex in schizophrenia (Beasley and Reynolds, Schizophrenia Research, 1997, 24; 349-355), however Kv3.1, Kv3.2 and Kv3.3 expression as not been investigated in this disease state.  
       [0004] The Shaw-related voltage-gated potassium channels are known to have many names (see below).  
                                       Present Nomenclature   Splice Variants           (Alternate names)   (Alternate names)   Gene                  Kv3.1   Kv3.1a   KCNC1       (KShIIIB; NGK2-KV4)   (NGK2; KShIIIB)           Kv3.1b           (KV4)       Kv3.2   Kv3.2a   KCNC2       (KShIIIA)   (RKShIIIA; KShIIIA.1)           Kv3.2b           (KShIIIA.3)           Kv3.2d           (KShIIIA.2)       Kv3.3   Kv3.3a   KCNC3       (KShIIID)   (KShIIID.1)           Kv3.3b           (KShIIID.2)                  
 
       [0005] Table adapted from Weiser et al., The Journal of Neuroscience, March 1994, 14(3); 949-972.  
       [0006] In the present specification, the inventors use the name Kv3.1 for the voltage-gated potassium channel 3.1; Kv3.2 for the voltage-gated potassium channel 3.2 and Kv3.3 for the voltage-gated potassium channel 3.3. Alternate splice variants of each of the Kv3 genes given in the table above), with the splice variants for each gene differing only in their intracellular C-terminal sequence (Coetzee et al., Annals of the New York Academy of Sciences, 1999, 868; 233-285.  
       [0007] The human Kv3 genes have also been cloned. Kv3.1 α-subunit: GenBank accession number NM — 004976; Localization of a highly conserved human potassium channel gene (NGK2-Kv4; KCNCl) to chromosome 11p15. Reid T; Rudy B; Vega-Saenz de Miera E; Lau D; Ward D C and Sen K. (1993). Genomics 15 (2), 405-411. The Kv3.1a α-subunit displays ˜99% sequence identity to the rat sequence, and there is &gt;90% sequence identity between rat and mouse sequences. Kv3.2: GenBank accession number AY118169. Kv3.3:GenBank accession number NM — 004977; Genomic organization, nucleotide sequence and cellular distribution of a Shaw-related potassium channel gene, Kv3.3, and mapping of Kv3.3 and Kv3.4 to human chromosomes 19 and 1. Ghanshani et al., Genomics 12(2) 1992; 190-196)  
       [0008] Chronic treatment with phencyclidine (hereinafter PCP) in the rat provides an animal model of schizophrenia with superior face, construct and predictive validity (WO01/75440). It has been shown to mimic metabolic changes (metabolic hypofunction in the prefrontal cortex, thalamus and auditory structures) that are observed in schizophrenic patients, that can be correlated to both positive and negative symptomology and cognitive deficits associated with the disease, and also neurochemical changes observed in postmortem tissue from schizophrenic patients such as decreased parvalbumin expression and decreased 5HT2A binding. Parvalbumin mRNA was selectively decreased within certain brain regions in the chronic PCP rat model of schizophrenia, the prelimbic region of the prefrontal cortex and the reticular nucleus of the thalamus and this effect was modulated by chronic antipsychotic treatment. Due to the high degree of co-localization between parvalbumin and the Kv3.1 and Kv3.3 channels, the aim was to determine whether Kv3.1 α-subunit expression is similarly altered by the same chronic PCP rat model of schizophrenia. Also, due to the localization of Kv3.2 channels in thalamic relay neurons and GABAergic interneurons, it was also of interest whether Kv3.2 mRNA expression was also altered by the chronic PCP rat model of schizophrenia.  
       SUMMARY OF THE INVENTION  
       [0009] The present inventors have found that the Kv3.1 α-subunit ene, or a nucleotide having SEQ ID NO:1; the Kv3.2 gene, or nucleotide having SEQ ID NO:3; and Kv3.3 gene, or a nucleotide having SEQ ID NO:5 show, altered expression in the brain of the chronic PCP rat model of schizophrenia, and also found that the nucleotides and the protein that these nucleotides encodes are useful for the diagnosis or treatment of schizophrenia. The present invention also provides a method of screening a compound that regulates expression and activity of this nucleotide and/or protein. Accordingly, the present invention provides the following.  
       [0010] (1) A method for diagnosing schizophrenia, which comprises use of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof, and a polynucleotide having a sequence complementary to such sequence, as an index of schizophrenia.  
       [0011] (2) The method of the above-mentioned (1), wherein the at least one kind of polynucleotide is selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.  
       [0012] (3) The method of the above-mentioned (1), wherein the at least one kind of polynucleotide is a polynucleotide having SEQ ID NO:1.  
       [0013] (4) A method for diagnosing schizophrenia, which comprises use of at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof, as an index of schizophrenia.  
       [0014] (5) The method of the above-mentioned (4), wherein the at least one kind of polypeptide is selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3 and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.  
       [0015] (6) The method of the above-mentioned (4), wherein the at least one kind of polypeptide is a polypeptide encoded by the polynucleotide of SEQ ID NO:1.  
       [0016] (7) A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof and a polynucleotide having a sequence complementary 5 to such sequence.  
       [0017] (8) The method of the above-mentioned (7), wherein the expression of Kv3 channel is analyzed using at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a polynucleotide having a sequence complementary to such sequence.  
       [0018] (9) The method of the above-mentioned (7), wherein the expression of Kv3 channel is analyzed using a polynucleotide having SEQ ID NO:1.  
       [0019] (10) A method for identifying a compound modulating the activity of Kv3 channels, which comprises analyzing an expression of Kv3 channel using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, and a fragment thereof.  
       [0020] (11) The method of the above-mentioned (10), wherein the expression of Kv3 channels is analyzed using at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, and a polypeptide encoded by the polynucleotide of SEQ ID NO:5.  
       [0021] (12) The method of the above-mentioned (10), wherein the expression of Kv3 channel is analyzed using a polypeptide encoded by the polynucleotide of SEQ ID NO:1.  
       [0022] (13) A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of  
       [0023] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a fragment thereof, and whose expression is desired to be controlled;  
       [0024] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and  
       [0025] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).  
       [0026] (14) A method for screening a compound regulating the, expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of:  
       [0027] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of a polynucleotide having SEQ ID NO:1);  
       [0028] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and  
       [0029] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).  
       [0030] (15) A method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of:  
       [0031] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, and a polynucleotide having SEQ ID NO:5, and whose expression is desired to be controlled);  
       [0032] (b) detecting the expression of polynucleotide in the cell; and  
       [0033] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).  
       [0034] (16) A method for screening a compound regulating the expression of a polynucleotide having SEQ ID NO:1, which comprises the steps of:  
       [0035] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide having SEQ ID NO:1);  
       [0036] (b) detecting the expression of polynucleotide in the cell; and  
       [0037] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone). 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWING  
     [0038]FIG. 1 shows a chronic intermittent PCP treatment regime (YRING Model). 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0039] The present invention relates to methods for prognostic and/or diagnostic evaluation of schizophrenia and/or for the identification of subjects who are predisposed to schizophrenia, for example by examination of allelic variation of the gene identified herein in an individual or by determination of the expression of the gene in an individual. Furthermore, the invention provides methods for evaluating the efficacy of drugs for such disorders, and monitoring the progress of patient symptoms involved in clinical trials for the treatment of such disorders.  
     [0040] The invention further provides methods for the identification of compounds that modulate the expression of the Kv3 genes and/or the activity of the Kv3.1, Kv3.2 or Kv3.3 channels. Such identified compounds may be used in the treatment of schizophrenia.  
     [0041] By the “regulate” is meant here the action to promote or suppress the expression of the gene, which varies according to the desired effect. In consideration of the application to Schizophrenia, however, screening of a compound that increases the level of expression of Kv3.1 α-subunit gene is preferable and a compound that decreases the level of the Kv3.2 and Kv3.3 gene is preferable.  
     [0042] In the present invention, the “polynucleotide having a sequence complementary” means a sequence complementary to a target sequence to the extent that hybridization under stringent conditions occurs, wherein stringency can be appropriately determined according to the method employed.  
     [0043] In the present invention, the “fragment” means a poly(oligo)nucleotide or a poly(oligo)peptide obtained by fragmentation of polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a polypeptide encoded by the polynucleotide of SEQ ID NO:1 (i.e., SEQ ID NO:2), a polypeptide encoded by the polynucleotide of SEQ ID NO:3 (i.e., SEQ ID NO:4) or a polypeptide encoded by the polynucleotide of SEQ ID NO:5 (i.e., SEQ ID NO:6) to the extent that affords reproduction of characteristic mode of expression found in the pharmacology of schizophrenia. For example, the fragment may be any as long as the expression of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a polypeptide having SEQ ID NO:2, a polypeptide having SEQ ID NO:4 and a polypeptide having SEQ ID NO:6 in patients with schizophrenia can be observed and the size thereof is not particularly limited.  
     [0044] The “at least one kind of polynucleotide” of the “at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5, a fragment thereof, and a polynucleotide having a sequence complementary to the sequence” intends, in addition to each polynucleotide, two kinds of polynucleotides selected from the group, or 3 kinds of polynucleotides selected from the group and the like. It means, for example, one kind of, two kinds of and all three kinds of polynucleotides selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5. Likewise, the “at least one kind of polypeptide” of the “at least one kind of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3, a polypeptide encoded by the polynucleotide of SEQ ID NO:5, a fragment thereof, and a polypeptide having a sequence complementary to the sequence” intends, in addition to each polypeptide, two kinds of polypeptides selected from the group, or 3 kinds of polypeptides selected from the group and the like. It means, for example, one kind of, two kinds of and all three kinds of polypeptide selected from the group consisting of a polypeptide encoded by the polynucleotide of SEQ ID NO:1, a polypeptide encoded by the polynucleotide of SEQ ID NO:3 and a polypeptide encoded by the polynucleotide of SEQ ID NO:5. Preferably, it is a polynucleotide having SEQ ID NO:1 or polypeptide encoded by the polynucleotide of SEQ ID NO:1.  
     [0045] The present invention provides a method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, which comprises the steps of  
     [0046] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3, a polynucleotide having SEQ ID NO:5 and a fragment thereof and whose expression is desired to be controlled);  
     [0047] (b) detecting the expression of polypeptide encoded by the polynucleotide in the cell; and  
     [0048] (c) determining a compound promoting or suppressing the expression of the polypeptide as compared to a control (administration of vehicle alone).  
     [0049] In the above-mentioned screening method, the “test compound” is free of any particular limitation as long as it is the object compound for which capability of regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, preferably a polynucleotide having SEQ ID NO:1 is desired to be determined, and it may be a novel or known compound. A combination drug can be the object compound. More specifically, chronic PCP administration that affects the expression of the Kv3 mRNAs is combined with administration of the test compound. By analyzing the metabolic and neurochemical state induced by the chronic PCP administration and changes in the expression of the Kv3 mRNAs, the effect of the test compound can be investigated.  
     [0050] In the above-mentioned screening method, the cell is free of any particular limitation as long as it expresses at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, preferably a polynucleotide having SEQ ID NO:1. It may be naturally occurring or processed to express said polynucleotide by genetic recombination.  
     [0051] For detection of intracellular expression of polypeptide and comparison with control, the methods and techniques generally used in this field can be used and those of ordinary skill in the art can modify them suitably. Specific examples thereof include western blotting capable of detection at a protein level.  
     [0052] Moreover, the method for screening a compound regulating the expression of at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5, may comprise the steps of  
     [0053] (a) bringing a test compound into contact with a cell (as used herein, the cell is capable of expression of polynucleotide, which is at least one kind of polynucleotide selected from the group consisting of a polynucleotide having SEQ ID NO:1, a polynucleotide having SEQ ID NO:3 and a polynucleotide having SEQ ID NO:5 and whose expression is desired to be controlled);  
     [0054] (b) detecting the expression of polynucleotide in the cell; and  
     [0055] (c) determining a compound promoting or suppressing the expression of the polynucleotide as compared to a control (administration of vehicle alone).  
     [0056] Each term is as mentioned above, and for detection of intracellular expression of polynucleotide and comparison with control, the methods and techniques generally used in this field can be used and those of ordinary skill in the art can modify them suitably. Specific examples thereof include northern blotting capable of detection at an mRNA level.  
     [0057] The information obtained through the screening method and diagnostic method of the present invention (hereinafter to be generally referred to as characterization) can suggest relevant methods for the treatment or control of schizophrenia. For example, relevant treatment can include a regulation of gene expression and/or a modulation of gene product activity. Characterization procedures such as those described herein can indicate whether such regulation/modulation should be positive or negative. As used herein, “positive regulation/modulation” refers to an increase in gene expression and/or the activity of gene product of interest. “Negative regulation/modulation”, as used herein, refers to a decrease in gene expression and/or activity.  
     [0058] In vitro systems can be designed to identify compounds capable of binding with said Kv3 genes products of the invention.  
     [0059] SEQ ID NO:1 shows the nucleotide sequence of the rat Kv3.1 α-subunit gene of the present invention, SEQ ID NO:3 shows the nucleotide sequence of the rat Kv3.2 gene of the present invention and SEQ ID NO:5 shows the nucleotide sequence of the rat Kv3.3 gene of the present invention, which were observed to be differentially expressed in the brain in the chronic PCP rat model of schizophrenia.  
     [0060] SEQ ID NO:2 shows the amino acid sequence of the rat Kv3.1 α-subunit of the present invention, SEQ ID NO:4 shows the amino acid sequence of the rat Kv3.2 of the present invention and SEQ ID NO:6 shows the amino acid sequence of the rat Kv3.3 of the present invention which were observed to be differentially expressed in the brain in the chronic PCP rat model of schizophrenia.  
     [0061] SEQ ID NO:7 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.1 α-subunit mRNA; SEQ ID NO:8 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.2 mRNA; SEQ ID NO:9 shows the oligonucleotide (45mer) used for in situ hybridization for the Kv3.3 mRNA.  
     [0062] The present invention is explained in more detail in the following by way of Experiments, which are not to be construed as limitative.  
     [0063] In this specification, Y-931 means 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[l]benzothieno[2,3-b][1,5]benzo-diazepine monomaleate, which is known as an a typical antipsychotic drug (WO99/11647).  
     [0064] Experiment  
     [0065] Method  
     [0066] Experiment 1  
     [0067] Male Sprague-Dawley rats, weighing 224-260 g at the beginning of the study, were randomly assigned to one of ten treatment groups as follows: vehicle (0.02N HCl in saline)-vehicle (polyethyleneglycol); PCP-vehicle; PCP-Y-931 0.3 mg/kg/day; PCP-Y-931 1 mg/kg/day; PCP-Y-931 3 mg/kg/day; PCP-Y-931 10 mg/kg/day; PCP-olanzapine 0.3 mg/kg/day; PCP-olanzapine 1 mg/kg/day; PCP-olanzapine 3 mg/kg/day; PCP-olanzapine 10 mg/kg/day. The dose of PCP used was 2.24 mg/kg (free base equivalent, equal to 2.58 mg/kg PCP.HCl) and PCP was administered according to the chronic PCP rat model of schizophrenia (WO01/75440). Briefly, i.p. injections of PCP (2.24 mg/kg) or saline (1 ml/kg) were administered once daily on days 1-5, 8, 10, 12, 15, 17, 19, 22, 24, 26. Osmotic minipumps (2ML4 (28 day), Alzet) were implanted subcutaneously on day 8 prior to PCP injection to deliver doses of antipsychotics or vehicle detailed above for 21 days of drug treatment. The osmotic minipumps were primed in vitro for 24 hours in order to ensure pumping started immediately upon implantation.  
     [0068] 29 days after the first PCP injection, the animals were sacrificed, the brains removed and stored at −70° C. Osmotic minipumps were also removed and the dose administered was verified. The brains were sectioned at −20° C. using a cryostat (Leica, CM1850), with 14 μm coronal sections being thaw-mounted onto silanized slides (Dako, Japan) from the following bregma levels according to the Rat Brain Atlas, Paxinos and Watson (2000): 3.22 mm; 1.6 mm, −1.80 mm and −4.8 mm. The sections were then stored at −80° C. over silica gel until required. The oligonucleotide (45mer) used for in situ hybridization for the Kv3.1 α-subunit mRNA was 5′-ATAGTCGAAGTGGCTGTGGGCGTCCGGCTCCGCCAGCCAGGCAAG-3′ (SEQ ID NO:7) complementary to bases 1261-1305 of the rat Kv3.1 α-subunit (GenBank Accession Number NM — 012856; Luneau et al., Proc. Natl. Acad. Sci. USA. 1991, 88; 3932-3936). This probe sequence recognizes both alternate splice variants (Kv3.1a and Kv3.1b) of the Kv3.1 channel. The probe was 3′ end-labeled with terminal deoxyribonucleotidyl transferase (Boehringer Mannheim) and with the isotope  5-α-   35 S-dATP (Amersham, specific activity &gt;1000 Ci/mmol) and incubated at 37° C. for one hour. The reaction was terminated by addition of 40 μl diethyl pyrocarbonate (DEPC)-treated water. The probe was purified using the QIAquick nucleotide removal kit (Qiagen). The extent of probe labeling was assessed using scintillation counting, and probes labeled from 100,000 to 300,000 d.p.m. μl −1  were used for in situ hybridization. On the day of the in situ hybridization experiment the sections were fixed in 4% paraformaldehyde-0.1M phosphate buffer for 30 mins at 4° C., rinsed twice for 5 mins in 0.1M phosphate buffer saline (PBS), acetylated with 0.25% acetic anhydride in 0.1M triethanolamine for 10 mins, rinsed twice for 5 mins in 2×SSC (0.15M NaCl, 15 mM sodium citrate), dehydrated and delipidated through a graded series of ethanol and chloroform. The sections were then air dried and then hybridized overnight at 42° C. with 0.2-1×10 −6  d.p.m. of the labeled probe in 100 μl of hybridization solution (Hybrisol 1, Intergen) containing 0.1M dithiothreitol. After hybridization, the sections were washed twice for 10 secs in 1×SSC at 55° C., four times for 15 mins in 1×SSC at 55° C., for 1 hour in 1×SSC at room temperature and twice in water for 5 mins. The sections were then dipped successively in 60%, 80%, 90%, 95% and 100% ethanol and air dried. The sections were exposed to BAS 5000 image plates and developed after 7 days. Kv3.1 α-subunit mRNA expression was quantified using a computer-based densitometry system (MCID 5, Canada). Statistical analysis of the data was performed using a students t-test (vehicle-vehicle vs PCP-vehicle) followed by Dunnett&#39;s Method (PCP-vehicle vs PCP-antipsychotics). Statistical significance was defined as p&lt;0.05.  
     [0069] Experiment 2  
     [0070] In a second experiment using different method for in situ hybridisation, the effect of chronic PCP treatment on Kv3.1, Kv3.2 and Kv3.3 mRNA were examined. 20 male hooded Long Evans rats (250-300 g at the beginning of the study, Harlan UK) were randomly assigned to either vehicle (saline, n=10) or PCP (2.58 mg/kg PCP.HCl, n=10) treatment groups. Animals were treated according to the YRING model (FIG. 1) and killed by cervical dislocation 72 hours after the last exposure to PCP. The brains were stored at −70° C. until required.  
     [0071] In Situ Hybridisation  
     [0072] 20 μm coronal sections were cut on a cryostat at −20° C. and collected onto poly-L-lysine coated slides. The sections were fixed, dehydrated and stored under ethanol at 4° C. until required. 45mer oligonucleotide probes designed against rat mRNA for parvalbumin (GeneBank Accession number NM — 022499, bases 223-267), Kv3.1 (GeneBank Accession number NM — 012856, bases 1261-1305; SEQ ID NO: 7), Kv3.2 (GeneBank Accession number NM — 139217, bases 1021-1065; SEQ ID NO: 8) and Kv3.3 (GeneBank Accession number NM 053997, bases 241-285; SEQ ID 30 NO: 9) were 3′ end-labeled with terminal deoxyribonucleotidyl transferase and  35 Sd-ATP. On the day of in situ hybridization, the sections from the chronic study were allowed to dry at room temperature then hybridized with the appropriate probe overnight at 42° C. The sections were then washed, dehydrated and air-dried before being exposed to x-ray film for 7-10 days.  
     [0073] The quantification of mRNA expression was carried out using computer-based densitometry (MCID 5). Bilateral relative optical density measurements were taken from duplicate sections from each animal (n=8-10 per treatment group for the chronic study). The results were analyzed using individual t-tests for each brain region. Statistical significance was defined as p&lt;0.05, again after correction for multiple comparisons using the sequential Bonferroni correction factor.  
     [0074] Results  
     [0075] Experiment 1  
     [0076] Table 1 shows the effect of chronic PCP and antipsychotic treatment on Kv3.1 α-subunit mRNA expression. Chronic PCP treatment selectively decreased Kv3.1 α-subunit mRNA expression within the prelimbic region of the prefrontal cortex (PrL, −31%), the dorsal part of the reticular nucleus of the thalamus (dRt, −15%) and the dorsolateral striatum (DLStr, −16%). Within the PrL, both Y-931 and olanzapine, at all doses administered, significantly reversed the PCP-induced decrease back to control levels. However, within the dRt and the DLStr, neither Y-931 nor olanzapine significantly modulated the PCP-induced effect.  
     [0077] Compared to PCP-vehicle, PCP-olanzapine treatment (1 mg/kg/day, only) produced a significant decrease in Kv3.1 α-subunit mRNA expression within the granule cell layer of the dentate gyrus (DGgcl) and a significant increase in Kv3.1 α-subunit mRNA expression within the ventromedial striatum (VMStr) (0.3 &amp; 3 mg/kg/day olanzapine, only).  
     [0078] Experiment 2  
     [0079] Table 2 shows the levels of Kv3.1 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. Very selective changes in Kv3.1 mRNA expression were observed after chronic intermittent exposure to PCP. A significant decrease in Kv3.1 mRNA expression was observed within the prelimbic cortex (−23%) and within the ventral part of the reticular thalamic nucleus (−19%). No other changes were observed in any other regions.  
     [0080] Table 3 shows the levels of Kv3.2 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. A significant increase in Kv3.2 mRNA expression was observed within the prelimbic cortex (+16%) 1 and the primary motor cortex (+13%). A small but significant decrease in Kv3.2 mRNA expression was also observed within the anteromedial thalamic nucleus (−9%). No significant changes were observed after chronic intermittent PCP treatment within any other regions.  
     [0081] Table 3 shows the levels of Kv3.3 mRNA expression within the rat brain after chronic intermittent treatment according to the YRING model. Within cortical regions, an increase in Kv3.3 mRNA expression after chronic intermittent exposure to PCP was observed within the prelimbic cortex (+18%) and the ventral orbital cortex (+14%). A significant increase in Kv3.3 mRNA expression was also observed within the anterodorsal thalamic nucleus (+21%) and the ventral part of the reticular thalamic nucleus (+33%). No other changes were observed in any other regions.  
                           TABLE 1                                      PCP-Y-931   PCP-Olanzapine                                                                     0.3   1   3   10   0.3   1   3   10       Region   Veh-Veh   PCP-Veh   mg/kg/day   mg/kg/day   mg/kg/day   mg/kg/day   mg/kg/day   mg/kg/day   mg/kg/day   mg/kg/day               PrL   14.22 ± 0.21    9.83 ±   12.76 ±   12.17 ±   12.93 ±   12.55 ±   12.50 ±   12.78 ±   13.18 ±   12.66 ±                0.23**    0.62††    0.85†    0.33††    0.67†    0.92††    0.54††    0.43††    0.49††       IL   12.30 ± 0.58   12.28 ±   11.64 ± 0.40   11.33 ± 0.60   12.91 ± 0.38   11.55 ± 0.45   12.00 ± 0.65   11.27 ± 1.08   11.40 ± 0.41   12.15 ± 0.62                0.82       M1   16.68 ± 1.06   15.88 ±   15.33 ± 0.38   14.81 ± 0.80   17.01 ± 0.75   16.51 ± 0.67   15.83 ± 0.69   16.17 ± 1.27   16.17 ± 0.79   16.27 ± 0.37                1.53       M2   14.49 ± 0.65   14.38 ±   13.23 ± 0.29   13.10 ± 0.57   14.25 ± 0.81   13.04 ± 0.53   13.72 ± 0.78   12.57 ± 0.94   14.48 ± 0.90   13.14 ± 0.99                0.89       VO   18.42 ± 0.99   19.85 ±   19.12 ± 0.74   17.81 ± 1.08   19.32 ± 0.63   18.51 ± 1.08   19.03 ± 1.00   18.35 ± 1.04   18.96 ± 0.86   19.88 ± 0.58                0.85       IO   16.05 ± 0.96   16.48 ±   17.52 ± 0.95   15.49 ± 0.30   17.52 ± 0.36   15.30 ± 0.62   15.50 ± 0.51   16.18 ± 0.32   16.83 ± 0.79   17.74 ± 0.37                0.69       ACg   14.97 ± 0.84   15.01 ±   15.36 ± 0.29   15.10 ± 0.92   15.40 ± 0.83   14.82 ± 0.74   15.83 ± 0.73   14.83 ± 1.00   16.31 ± 0.40   15.03 ± 0.72                0.54       Pir   37.64 ± 1.18   40.65 ±   38.95 ± 2.38   43.16 ± 2.76   38.15 ± 3.31   41.69 ± 1.90   37.73 ± 1.18   36.82 ± 0.51   43.78 ± 1.20   40.66 ± 2.21                1.64       RSg   18.63 ± 1.60   20.38 ±   20.89 ± 0.95   19.99 ± 0.59   20.73 ± 1.22   19.48 ± 0.64   19.48 ± 0.72   19.43 ± 1.20   20.96 ± 1.08   19.59 ± 0.92                1.32       RSa   15.81 ± 1.42   17.96 ±   19.22 ± 1.40   18.90 ± 1.03   17.36 ± 1.55   18.04 ± 0.87   16.53 ± 1.13   16.92 ± 0.74   18.21 ± 1.15   18.77 ± 1.07                1.43       Au1   16.42 ± 1.46   18.08 ±   17.02 ± 1.26   18.48 ± 1.36   16.76 ± 0.32   17.98 ± 0.68   18.60 ± 1.75   18.68 ± 0.80   17.42 ± 1.46   16.91 ± 0.86                1.04       DGgd   34.86 ± 2.50   38.63 ±   38.38 ± 1.53   39.21 ± 1.75   36.93 ± 2.53   36.11 ± 2.06   35.22 ± 1.16   33.04 ±   36.51 ± 1.07   38.16 ± 1.10                1.47                        2.15†       CA1pd   16.98 ± 1.79   15.90 ±   16.80 ± 1.23   18.34 ± 0.91   16.47 ± 0.98   19.18 ± 2.03   19.98 ± 1.59   19.14 ± 2.06   18.37 ± 1.54   20.15 ± 1.22                0.97       CA2pd   21.38 ± 1.27   18.61 ±   24.07 ± 1.74   20.07 ± 1.71   21.47 ± 2.23   22.31 ± 1.57   21.36 ± 2.52   17.72 ± 1.86   24.21 ± 1.23   20.59 ± 1.35                1.29       CA3pd   31.46 ± 1.68   32.94 ±   34.10 ± 1.52   33.99 ± 3.29   34.72 ± 1.24   33.90 ± 2.52   33.71 ± 3.48   30.50 ± 1.94   33.46 ± 2.04   32.81 ± 1.82                2.69       dRt   56.97 ± 2.24   48.80 ±   54.94 ± 1.99   51.68 ± 2.34   53.38 ± 2.99   54.81 ± 1.90   50.99 ± 2.22   50.92 ± 3.80   52.87 ± 1.95   52.42 ± 1.19                2.72*       vRt   46.12 ± 3.47   45.07 ±   46.91 ± 2.73   47.18 ± 2.10   52.57 ± 2.00   49.70 ± 2.76   54.57 ± 3.12   46.70 ± 3.99   42.97 ± 2.22   53.69 ± 2.07                2.26       DLStr    6.98 ± 0.20    5.87 ±    6.55 ± 0.53    5.99 ± 0.96    7.13 ± 0.70    7.46 ± 0.86    6.87 ± 0.38    6.99 ± 0.43    6.84 ± 0.42    6.70 ± 0.59                0.44*       VMStr    6.80 ± 0.20    6.15 ±    6.75 ± 0.50    7.18 ± 0.71    7.69 ± 0.35    7.23 ± 0.26    7.33 ±    6.88 ± 0.46    7.52 ±    5.99 ± 0.28                0.23                    0.24†        0.16††       SN   12.47 ± 0.55   12.82 ±   11.66 ± 0.91   12.98 ± 1.12   13.04 ± 1.29   15.34 ± 1.58   13.27 ± 1.21   13.98 ± 0.96   13.09 ± 0.44   12.54 ± 0.68                1.09       AcbC   8.57 ± 0.53   8.48 ±   7.65 ± 0.40   8.40 ± 0.63   8.44 ± 0.43   8.42 ± 0.53   8.59 ± 0.58   8.12 ± 0.67   8.55 ± 0.25   8.27 ± 0.31                0.51       AcbS   10.01 ± 0.67   10.62 ±   10.24 ± 0.64   11.55 ± 0.50   11.11 ± 0.27   11.26 ± 0.67   11.42 ± 0.73   10.43 ± 0.56   11.62 ± 0.84   11.95 ± 1.02                0.61       MM   25.86 ± 1.87   24.34 ±   25.02 ± 2.54   24.82 ± 0.93   20.92 ± 0.93   28.12 ± 1.89   25.36 ± 2.25   25.76 ± 1.27   25.24 ± 2.32   4.69 ± 2.24                2.53       MG   25.23 ± 1.50   26.93 ±   26.82 ± 1.55   26.36 ± 0.95   26.75 ± 2.02   27.36 ± 1.86   26.64 ± 2.22   25.50 ± 1.46   24.56 ± 1.41   25.78 ± 0.77                1.46                                  
 
     [0082]               TABLE 2                          Kv3.1 mRNA expression in rat brain after chronic       intermittent exposure to vehicle or PCP (YRING model).                         Relative Optical Density (ROD)                                     PCP           Brain Region   Vehicle   (2.58 mg/kg)   % Control               Cortical                   Regions       PrL   0.112 ± 0.002   0.086 ± 0.004**    77 ± 4**       IL   0.103 ± 0.003   0.098 ± 0.004    95 ± 4       vO   0.122 ± 0.003   0.122 ± 0.004   100 ± 3       lO   0.101 ± 0.003   0.092 ± 0.003    91 ± 3       M1   0.123 ± 0.004   0.120 ± 0.004    98 ± 3       M2   0.116 ± 0.002   0.106 ± 0.004    91 ± 3       ACg   0.126 ± 0.006   0.116 ± 0.004    92 ± 3       Pir   0.263 ± 0.006   0.243 ± 0.014    92 ± 5       RSG   0.148 ± 0.006   0.153 ± 0.008   103 ± 5       RSA   0.127 ± 0.005   0.135 ± 0.006   106 ± 5       Au1   0.138 ± 0.008   0.137 ± 0.009    99 ± 6       LEnt   0.096 ± 0.008   0.093 ± 0.005    97 ± 5       Thalamus       AD   0.215 ± 0.006   0.216 ± 0.006   100 ± 3       dRt   0.274 ± 0.007   0.258 ± 0.013    94 ± 5       vRt   0.275 ± 0.010   0.224 ± 0.008**    81 ± 3**       Hippocampus       DG gcl   0.244 ± 0.005   0.239 ± 0.012    98 ± 5       CA1pcl   0.128 ± 0.006   0.122 ± 0.007    95 ± 5       CA2pcl   0.156 ± 0.009   0.156 ± 0.010   100 ± 6       CA3pcl   0.202 ± 0.007   0.203 ± 0.009   100 ± 4                                    
     [0083]               TABLE 3                          Kv3.2 mRNA expression in rat brain after chronic       intermittent exposure to vehicle or PCP (YRING model).                         Relative Optical Density (ROD)                                             PCP               Brain Region   Vehicle   (2.58 mg/kg)   % Control                       Cortical                       Regions           PrL   0.079 ± 0.002   0.092 ± 0.003*   116 ± 4           IL   0.079 ± 0.003   0.083 ± 0.002   105 ± 2           vO   0.074 ± 0.002   0.078 ± 0.003   105 ± 4           lO   0.069 ± 0.002   0.073 ± 0.002   106 ± 3           M1   0.067 ± 0.002   0.076 ± 0.003*   113 ± 4           M2   0.076 ± 0.003   0.079 ± 0.004   104 ± 5           ACg   0.078 ± 0.002   0.075 ± 0.002    96 ± 2           Pir   0.140 ± 0.005   0.138 ± 0.006   98 ± 4           RSG   0.065 ± 0.004   0.069 ± 0.002   106 ± 3           RSA   0.070 ± 0.002   0.065 ± 0.002    93 ± 3           Au1   0.070 ± 0.002   0.068 ± 0.003    97 ± 4           LEnt   0.051 ± 0.003   0.048 ± 0.002    94 ± 4           Thalamus           AV   0.275 ± 0.006   0.269 ± 0.005    98 ± 2           AM   0.248 ± 0.005   0.227 ± 0.006*    91 ± 2           MD   0.211 ± 0.008   0.187 ± 0.010    89 ± 5           VA   0.240 ± 0.008   0.223 ± 0.006    93 ± 2           VM   0.206 ± 0.009   0.201 ± 0.005    98 ± 2           VL   0.211 ± 0.010   0.208 ± 0.004    98 ± 2           LDVL   0.194 ± 0.009   0.197 ± 0.004   102 ± 2           LDDM   0.203 ± 0.008   0.205 ± 0.007   101 ± 3           VPL   0.175 ± 0.007   0.180 ± 0.005   103 ± 3           MGD   0.175 ± 0.006   0.164 ± 0.006    94 ± 3           MGV   0.193 ± 0.007   0.185 ± 0.003    96 ± 2           DLG   0.195 ± 0.012   0.222 ± 0.007   114 ± 4           Hippocampus           DG gcl   0.097 ± 0.004   0.095 ± 0.007    98 ± 7           CA1pcl   0.069 ± 0.004   0.075 ± 0.004   109 ± 6           CA2pcl   0.080 ± 0.002   0.082 ± 0.003   102 ± 4           CA3pcl   0.142 ± 0.005   0.134 ± 0.005    94 ± 4                                                
     [0084]               TABLE 4                          Kv3.3 mRNA expression in rat brain after chronic       intermittent exposure to vehicle or PCP (YRING model).                         Relative Optical Density (ROD)                                     PCP           Brain Region   Vehicle   (2.58 mg/kg)   % Control               Cortical Regions                   PrL   0.057 ± 0.002   0.067 ± 0.003*   118 ± 5       IL   0.053 ± 0.002   0.059 ± 0.002   111 ± 4       vO   0.073 ± 0.003   0.083 ± 0.003*   114 ± 4       lO   0.053 ± 0.002   0.058 ± 0.002   109 ± 4       M1   0.085 ± 0.003   0.093 ± 0.002   109 ± 2       M2   0.073 ± 0.002   0.075 ± 0.003   103 ± 4       ACg   0.068 ± 0.003   0.069 ± 0.003   101 ± 4       Pir   0.111 ± 0.005   0.115 ± 0.006   104 ± 5       RSG   0.087 ± 0.004   0.092 ± 0.004   106 ± 4       RSA   0.066 ± 0.003   0.067 ± 0.003   102 ± 4       Au1   0.075 ± 0.002   0.076 ± 0.003   101 ± 4       LEnt   0.042 ± 0.002   0.047 ± 0.002   112 ± 5       Thalamus       AD   0.173 ± 0.009   0.209 ± 0.001*   121 ± 1       dRt   0.186 ± 0.001   0.198 ± 0.006   106 ± 3       vRt   0.121 ± 0.010   0.161 ± 0.007*   133 ± 6       Hippocampus       DG gcl   0.254 ± 0.009   0.275 ± 0.011   108 ± 4       CA1 pcl   0.144 ± 0.006   0.146 ± 0.006   101 ± 4       CA2 pcl   0.149 ± 0.005   0.148 ± 0.007    99 ± 5       CA3 pcl   0.204 ± 0.006   0.210 ± 0.006   103 ± 3                                    
     [0085] Abbreviations:  
     [0086] PrL, prelimbic cortex;  
     [0087] IL, infralimbic cortex;  
     [0088] M1, primary motor cortex;  
     [0089] M2, secondary motor cortex;  
     [0090] vO, ventral orbital cortex;  
     [0091] lO, lateral orbital cortex;  
     [0092] Acg, anterior cingulate cortex;  
     [0093] Pir, piriform cortex;  
     [0094] RSg, granular retrosplenial cortex;  
     [0095] Rsa, agranular retrosplenial cortex;  
     [0096] Aul, primary auditory cortex;  
     [0097] LEnt, lateral entorhinal cortex;  
     [0098] DGgcl, granule cell layer of the dentate gyrus;  
     [0099] CA1-CA3 pcl, pyramidal cell layer of the CA1-CA3 fields of  
     [0100] the hippocampus;  
     [0101] AD, anterodorsal nucleus of the thalamus;  
     [0102] AV, anteroventral nucleus of the thalamus;  
     [0103] AM, ateromedial nucleus of the thalamus;  
     [0104] MD, mediodorsal nucleus of the thalamus;  
     [0105] VA, ventral anterior nucleus of the thalamus;  
     [0106] VM, ventral medial nucleus of the thalamus;  
     [0107] VL, ventral lateral nucleus of the thalamus;  
     [0108] LDVL, laterodorsal thalamic nucleus, ventrolateral part;  
     [0109] LDDM, laterodorsal thalamic nucleus, dorsomedial part;  
     [0110] VPL, ventral posterolateral nucleus of the thalamus;  
     [0111] MGD, medial genicluate nucleus, dorsal part;  
     [0112] MGV, medial genicluate nucleus, ventral part;  
     [0113] DLG, dorsal lateral geniculate nucleus  
     [0114] dRt, vRt, dorsal and ventral parts of the reticular nucleus of the thalamus.  
     [0115] DLStr, dorsolateral striatum;  
     [0116] VMStr, ventromedial striatum;  
     [0117] SN, substantia nigra;  
     [0118] AcbC, nucleus accumbens core;  
     [0119] AcbS, nucleus accumbens shell;  
     [0120] MM, mammillary body;  
     [0121] MG, medial geniculates.  
     [0122] The decrease in Kv3.1 α-subunit mRNA expression observed in these studies parallel the selective changes previously observed in parvalbumin mRNA expression within the prelimbic cortex and the reticular nucleus of the thalamus. Moreover, the PCP-induced decreases in Kv3.1 α-subunit mRNA expression were reversed by chronic co-administration of Y-931 and olanzapine, as were PCP-induced changes in parvalbumin mRNA expression. Since parvalbumin expression is altered within the prefrontal cortex of schizophrenic patients and in rats after treatment with chronic PCP, these data suggest that Kv3.1 α-subunit mRNA may also be altered within schizophrenia in a similar manner.  
     [0123] As the chronic model of schizophrenia also produces an increase in Kv3.2 and Kv3.3 mRNA expression in the rat, these data suggest that Kv3.2 and Kv3.3 mRNA may also be altered in schizophrenia.  
     [0124] Drugs acting at the Kv3 channels have potential therapeutic roles in Schizophrenia. The hypothesis is that the decrease in Kv3.1 mRNA may affect the firing activity of the GABAergic interneurons in which it is located, which further contributes to an imbalance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex (which may be linked to negative symptoms and cognitive dysfunction). The changes in Kv3.2 mRNA suggest that thalamic relay neurons may also be mis-firing, which again may contribute to an imbalance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex. The changes in Kv3.3 mRNA may also disrupt the balance between the excitatory (glutamatergic) and inhibitory (GABAergic) pathways within the prefrontal cortex.  
     [0125] A drug which can restore Kv3.1, Kv3.2 and Kv3.3 expression may restore GABAergic interneuron activity back to normal.  
     [0126] Kv3.1 may be a good marker for the screening of antipsychotic activity because of the reversal with the a typical antipsychotic olanzapine and Y-931 as shown in these data.  
     [0127] This application is based on application No.02007114.8 filed in EPC, the contents of which are incorporated hereinto by reference.  
 
    
     
       
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                                                SEQUENCE LISTING  
               
               
                   
               
               
                   
               
               
                 &lt;160&gt; NUMBER OF SEQ ID NOS: 9  
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 1  
               
               
                 &lt;211&gt; LENGTH: 3977  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: CDS  
               
               
                 &lt;222&gt; LOCATION: (1162)..(2919)  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: gene  
               
               
                 &lt;222&gt; LOCATION: (1)..(3977)  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: polyA_signal  
               
               
                 &lt;222&gt; LOCATION: (3958)..(3963)  
               
               
                 &lt;300&gt; PUBLICATION INFORMATION:  
               
               
                 &lt;301&gt; AUTHORS: Luneau,C.J., Williams,J.B., Marshall,J., Levitan,E.S.,  
               
               
                       Oliva,C., Smith,J.S., Antanavage,J., Folander,K., Stein,R.B.,  
               
               
                       Swanson,R., Kaczmarek,L.K. and Buhrow,S.A.  
               
               
                 &lt;302&gt; TITLE: Alternate splicing contributes to K+ channel diversity in  
               
               
                       the mammalian central nervous system.  
               
               
                 &lt;303&gt; JOURNAL: Proc. Natl. Acad. Sci. USA.  
               
               
                 &lt;304&gt; VOLUME: 88  
               
               
                 &lt;305&gt; ISSUE: 5  
               
               
                 &lt;306&gt; PAGES: 3932-3936  
               
               
                 &lt;308&gt; DATABASE ACCESSION NUMBER: NM_012856  
               
               
                 &lt;309&gt; DATABASE ENTRY DATE: 1991-05-01  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 1  
               
               
                   
               
               
                 gaacgagcaa gcgagcaggc agcggagcag cagcccggag gcagcagcgg cggcggtggt     60  
               
               
                   
               
               
                 ggcggcagtg gccgctccgc gcctcgcctc cctggcctcg ccagcctcgt tgcgccgcgc    120  
               
               
                   
               
               
                 ccggacctgc cacccccgcc taccgggccc gacctcggca gcgcccctcg catcggctgc    180  
               
               
                   
               
               
                 cagcgccacc cgccctccca gagcagtgag cggagtgcgg ggcgcagaaa caccggagcc    240  
               
               
                   
               
               
                 agtgcccgcc agccccgcca agcaaaacgg gctgagagaa cctacgctcg gcccagcgcg    300  
               
               
                   
               
               
                 gctccacagc cgtccgggag ctgtcccttc agcaccgccg cggaagcctg agtcccagcg    360  
               
               
                   
               
               
                 cagcccagcg gaacccctga cccagcccga gcgcaccagg cgctgcgctt agcggcagcc    420  
               
               
                   
               
               
                 ccgcggggag cacccttgtg cccctaccca ggggacctgc catctcctcc gggaggcggg    480  
               
               
                   
               
               
                 gagaaggaac gaggagggag gtcgggcagc ttcacccgcc accgagggga gtaggcagac    540  
               
               
                   
               
               
                 aagcaaggag atccgaaggg gatcggtcac gcagggagga gagcaagccg catccgtccc    600  
               
               
                   
               
               
                 caccgcaccg ggagcgcgct gcggcgacca ccgcagagcc aagcgcggat ttctcgtaac    660  
               
               
                   
               
               
                 cccctctttc ctagcagggg ctggtctatc ggtccggccc ccgaaacgga gcagctgacc    720  
               
               
                   
               
               
                 ttcccctaaa aagctttgtg tcgatttctc catttttccc gctgagatgg taccgggagc    780  
               
               
                   
               
               
                 ccggcccccc catcatctct cccctcctcc cgggcctcgc cgctgagcgc cgccccactc    840  
               
               
                   
               
               
                 ccttcctccc tccctcttta cctccctcct ctcttccact gcctcctccg cagccaggcc    900  
               
               
                   
               
               
                 agctccctct cacactaggc gccttaaaga ccctaaggag cccgcgcaca cacccctgga    960  
               
               
                   
               
               
                 cccgcacctg actgacagct ccccctgagg gggcttggct cgttggttgg ggtgggtggc   1020  
               
               
                   
               
               
                 cagagccgcg gtcctctgtg ccccccgacg gctgggggga ggggggaaga ggccctgcgc   1080  
               
               
                   
               
               
                 ccccctcccc gtcgccaact ccccctggcg gcagctccca tgggtgtcgc tgggccgcgc   1140  
               
               
                   
               
               
                 catgcctaag ggggcgccgc g atg ggc caa ggg gac gag agc gag cgc atc     1191  
               
               
                                         Met Gly Gln Gly Asp Glu Ser Glu Arg Ile  
               
               
                                         1               5                   10  
               
               
                   
               
               
                 gtg atc aac gtg ggc ggc acg cgc cac cag acg tac cgc tcg acg ctg     1239  
               
               
                 Val Ile Asn Val Gly Gly Thr Arg His Gln Thr Tyr Arg Ser Thr Leu  
               
               
                                 15                  20                  25  
               
               
                   
               
               
                 cgc acg ctg ccc ggc acg cgg ctt gcc tgg ctg gcg gag ccg gac gcc     1287  
               
               
                 Arg Thr Leu Pro Gly Thr Arg Leu Ala Trp Leu Ala Glu Pro Asp Ala  
               
               
                             30                  35                  40  
               
               
                   
               
               
                 cac agc cac ttc gac tat gac ccg cgc gct gac gag ttc ttc ttc gac     1335  
               
               
                 His Ser His Phe Asp Tyr Asp Pro Arg Ala Asp Glu Phe Phe Phe Asp  
               
               
                         45                  50                  55  
               
               
                   
               
               
                 cgc cac ccg ggc gtc ttc gct cac atc ctg aac tat tac cgc acc ggc     1383  
               
               
                 Arg His Pro Gly Val Phe Ala His Ile Leu Asn Tyr Tyr Arg Thr Gly  
               
               
                     60                  65                  70  
               
               
                   
               
               
                 aag cta cac tgc ccg gcc gac gtg tgc ggg ccg ctc tac gag gag gag     1431  
               
               
                 Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Tyr Glu Glu Glu  
               
               
                 75                  80                  85                  90  
               
               
                   
               
               
                 ctg gcc ttc tgg ggc atc gac gag acg gac gtg gag ccc tgc tgc tgg     1479  
               
               
                 Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro Cys Cys Trp  
               
               
                                 95                  100                 105  
               
               
                   
               
               
                 atg acg tat cgc cag cac cgc gac gct gag gag gcg ctg gac agc ttt     1527  
               
               
                 Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe  
               
               
                             110                 115                 120  
               
               
                   
               
               
                 ggt ggc gcg ccc ttg gac aac agc gcc gac gac gcg gac gcc gac ggc     1575  
               
               
                 Gly Gly Ala Pro Leu Asp Asn Ser Ala Asp Asp Ala Asp Ala Asp Gly  
               
               
                         125                 130                 135  
               
               
                   
               
               
                 ccc ggc gac tcg ggc gac ggc gag gac gag ctg gag atg acc aag aga     1623  
               
               
                 Pro Gly Asp Ser Gly Asp Gly Glu Asp Glu Leu Glu Met Thr Lys Arg  
               
               
                     140                 145                 150  
               
               
                   
               
               
                 ttg gcg ctc agt gac tcc cca gat ggc cgg cct ggc ggc ttc tgg cgc     1671  
               
               
                 Leu Ala Leu Ser Asp Ser Pro Asp Gly Arg Pro Gly Gly Phe Trp Arg  
               
               
                 155                 160                 165                 170  
               
               
                   
               
               
                 cgc tgg cag cca cgc atc tgg gca ctg ttc gag gac ccc tac tca tcc     1719  
               
               
                 Arg Trp Gln Pro Arg Ile Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser  
               
               
                                 175                 180                 185  
               
               
                   
               
               
                 cgc tat gcg cgg tac gtg gcc ttt gcc tcc ctc ttc ttc atc ctg gtc     1767  
               
               
                 Arg Tyr Ala Arg Tyr Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Val  
               
               
                             190                 195                 200  
               
               
                   
               
               
                 tcc atc aca acc ttc tgt ctg gag acc cac gag cgc ttc aac ccc atc     1815  
               
               
                 Ser Ile Thr Thr Phe Cys Leu Glu Thr His Glu Arg Phe Asn Pro Ile  
               
               
                         205                 210                 215  
               
               
                   
               
               
                 gtg aac aag aca gaa att gag aac gtt cga aat ggc aca caa gtg cgg     1863  
               
               
                 Val Asn Lys Thr Glu Ile Glu Asn Val Arg Asn Gly Thr Gln Val Arg  
               
               
                     220                 225                 230  
               
               
                   
               
               
                 tac tac cgg gaa gcg gag acg gag gcc ttc ctc acc tac atc gag ggt     1911  
               
               
                 Tyr Tyr Arg Glu Ala Glu Thr Glu Ala Phe Leu Thr Tyr Ile Glu Gly  
               
               
                 235                 240                 245                 250  
               
               
                   
               
               
                 gtc tgc gtg gtc tgg ttc acc ttc gag ttc ctc atg cgt gtt gtc ttc     1959  
               
               
                 Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val Val Phe  
               
               
                                 255                 260                 265  
               
               
                   
               
               
                 tgt ccc aac aag gtg gag ttc atc aag aac tcc ctc aat atc att gac     2007  
               
               
                 Cys Pro Asn Lys Val Glu Phe Ile Lys Asn Ser Leu Asn Ile Ile Asp  
               
               
                             270                 275                 280  
               
               
                   
               
               
                 ttc gtg gcc atc ctc ccc ttc tac ctg gag gtg ggc cta agt ggc ctg     2055  
               
               
                 Phe Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu  
               
               
                         285                 290                 295  
               
               
                   
               
               
                 tcc tcc aaa gct gcc aag gac gtg cta ggc ttc ctg cgc gtc gtg cgc     2103  
               
               
                 Ser Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg  
               
               
                     300                 305                 310  
               
               
                   
               
               
                 ttc gtg cgc atc ctc cgt atc ttc aag ctg acc cgc cat ttt gtg ggc     2151  
               
               
                 Phe Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly  
               
               
                 315                 320                 325                 330  
               
               
                   
               
               
                 ctg cgg gtc ctg ggc cac acg ctc cgt gcc agc acc aac gag ttc ctg     2199  
               
               
                 Leu Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu  
               
               
                                 335                 340                 345  
               
               
                   
               
               
                 ctg ctt atc atc ttc ctg gcc ctg ggt gtg ctc atc ttt gcc acc atg     2247  
               
               
                 Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met  
               
               
                             350                 355                 360  
               
               
                   
               
               
                 atc tac tat gct gag agg ata ggg gca cag ccc aat gac ccc agc gcc     2295  
               
               
                 Ile Tyr Tyr Ala Glu Arg Ile Gly Ala Gln Pro Asn Asp Pro Ser Ala  
               
               
                         365                 370                 375  
               
               
                   
               
               
                 agc gaa cac aca cac ttt aaa aat atc ccc atc ggc ttc tgg tgg gct     2343  
               
               
                 Ser Glu His Thr His Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala  
               
               
                     380                 385                 390  
               
               
                   
               
               
                 gtg gtc acc atg acg aca ctg ggc tat gga gac atg tat cct cag acg     2391  
               
               
                 Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr  
               
               
                 395                 400                 405                 410  
               
               
                   
               
               
                 tgg tct ggg atg ttg gtg gga gca ctg tgc gcc ctg gct ggt gtg ctg     2439  
               
               
                 Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu  
               
               
                                 415                 420                 425  
               
               
                   
               
               
                 acc att gcc atg ccg gtg ccc gtc atc gtg aac aat ttt ggg atg tac     2487  
               
               
                 Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr  
               
               
                             430                 435                 440  
               
               
                   
               
               
                 tac tct tta gcc atg gct aag cag aaa cta cca aag aaa aaa aag aag     2535  
               
               
                 Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys Lys Lys  
               
               
                         445                 450                 455  
               
               
                   
               
               
                 cat att ccg cgg cca cca cag ctg gga tct ccc aat tat tgt aaa tct     2583  
               
               
                 His Ile Pro Arg Pro Pro Gln Leu Gly Ser Pro Asn Tyr Cys Lys Ser  
               
               
                     460                 465                 470  
               
               
                   
               
               
                 gtc gta aac tct cca cac cac agt act cag agt gac aca tgt ccg ctg     2631  
               
               
                 Val Val Asn Ser Pro His His Ser Thr Gln Ser Asp Thr Cys Pro Leu  
               
               
                 475                 480                 485                 490  
               
               
                   
               
               
                 gcc cag gaa gaa att tta gaa att aac aga gca gat tcc aaa ctg aat     2679  
               
               
                 Ala Gln Glu Glu Ile Leu Glu Ile Asn Arg Ala Asp Ser Lys Leu Asn  
               
               
                                 495                 500                 505  
               
               
                   
               
               
                 ggg gag gtg gcg aag gcc gcg ctg gcg aac gaa gac tgc ccc cac ata     2727  
               
               
                 Gly Glu Val Ala Lys Ala Ala Leu Ala Asn Glu Asp Cys Pro His Ile  
               
               
                             510                 515                 520  
               
               
                   
               
               
                 gac cag gcc ctc act ccc gat gag ggc ctg ccc ttt acc cgc tcg ggc     2775  
               
               
                 Asp Gln Ala Leu Thr Pro Asp Glu Gly Leu Pro Phe Thr Arg Ser Gly  
               
               
                         525                 530                 535  
               
               
                   
               
               
                 acc cgc gag aga tac gga ccc tgc ttc ctc tta tca acc ggg gag tac     2823  
               
               
                 Thr Arg Glu Arg Tyr Gly Pro Cys Phe Leu Leu Ser Thr Gly Glu Tyr  
               
               
                     540                 545                 550  
               
               
                   
               
               
                 gcg tgc ccg cct ggt gga gga atg aga aag gat ctt tgc aaa gaa agc     2871  
               
               
                 Ala Cys Pro Pro Gly Gly Gly Met Arg Lys Asp Leu Cys Lys Glu Ser  
               
               
                 555                 560                 565                 570  
               
               
                   
               
               
                 cct gtc att gct aag tat atg ccg aca gag gct gtg aga gtg act tga     2919  
               
               
                 Pro Val Ile Ala Lys Tyr Met Pro Thr Glu Ala Val Arg Val Thr  
               
               
                                 575                 580                 585  
               
               
                   
               
               
                 ccaggcggct tggccgagga cactggtggc tattaagcat ctgggtggac ctgcagcccc   2979  
               
               
                   
               
               
                 tcctcaccct cggacagagt aaattcacgc catgcaggtt tgccggacga gtccgagtgg   3039  
               
               
                   
               
               
                 ccccgggcat tgtactaaga cggacgtagc tttttctacg gcccacggta actgaccgta   3099  
               
               
                   
               
               
                 gaggattcgc ccttctttct tttgattttc tttttctttc tttttttttt ttttagaagt   3159  
               
               
                   
               
               
                 taccttttat ttggggaggg ggggtcaagg ggagccttag catgacttgc atgaagttaa   3219  
               
               
                   
               
               
                 acagaaaacc cagctaaacc aaccccacca gcccctgctg tgactgtatg ctcactctaa   3279  
               
               
                   
               
               
                 ccaccaccga gaaccagaga aaggcaagag tctcttattt cttccagcat tctttgacac   3339  
               
               
                   
               
               
                 gtagtgtcgg agtcaaactg tgacggcgct tggtagaacc ctgtacattt ccgggagtgg   3399  
               
               
                   
               
               
                 gtgcgggggg gggggggagg tcagggacta aggatggggc caggggagtg gattgctttt   3459  
               
               
                   
               
               
                 ttgtacacga gacccagagg aaaggtccca aaaaggcagt cagtcatcgg tcacattgac   3519  
               
               
                   
               
               
                 ctcaccttca tagctcacct ctcgctcgga aaaccaagaa ctatgctccg aataggattg   3579  
               
               
                   
               
               
                 tggaaattca cactgccacc ctcttccacc tccgtttggc atgcttgcga cccaatggac   3639  
               
               
                   
               
               
                 ctctccccaa gaccccgaca gcggctagtt taggtcaatt ctctcatctt ggtgtgtagc   3699  
               
               
                   
               
               
                 tccagtgtga ccaagtttca taacaaattg tttcatagtt acaccacatg gattttccaa   3759  
               
               
                   
               
               
                 tgtcatttta aagccaggat gtagagtccc tccagttcag gaccacccag aggggcgcct   3819  
               
               
                   
               
               
                 cccctccacc tttactaagg cgaaaaccga cactgtatgc aatttagtac ttcagagctc   3879  
               
               
                   
               
               
                 aaagaaaaaa aaaaaaagaa aaaaaaagaa aaaagaaaaa ctgcatgccc aatgttatgc   3939  
               
               
                   
               
               
                 aaagagattc gagcatgaaa taaattttgt aacatggt                           3977  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 2  
               
               
                 &lt;211&gt; LENGTH: 585  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 2  
               
               
                   
               
               
                 Met Gly Gln Gly Asp Glu Ser Glu Arg Ile Val Ile Asn Val Gly Gly  
               
               
                 1               5                   10                  15  
               
               
                   
               
               
                 Thr Arg His Gln Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr  
               
               
                             20                  25                  30  
               
               
                   
               
               
                 Arg Leu Ala Trp Leu Ala Glu Pro Asp Ala His Ser His Phe Asp Tyr  
               
               
                         35                  40                  45  
               
               
                   
               
               
                 Asp Pro Arg Ala Asp Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe  
               
               
                     50                  55                  60  
               
               
                   
               
               
                 Ala His Ile Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala  
               
               
                 65                  70                  75                  80  
               
               
                   
               
               
                 Asp Val Cys Gly Pro Leu Tyr Glu Glu Glu Leu Ala Phe Trp Gly Ile  
               
               
                                 85                  90                  95  
               
               
                   
               
               
                 Asp Glu Thr Asp Val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe Gly Gly Ala Pro Leu Asp  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 Asn Ser Ala Asp Asp Ala Asp Ala Asp Gly Pro Gly Asp Ser Gly Asp  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 Gly Glu Asp Glu Leu Glu Met Thr Lys Arg Leu Ala Leu Ser Asp Ser  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 Pro Asp Gly Arg Pro Gly Gly Phe Trp Arg Arg Trp Gln Pro Arg Ile  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Tyr Ala Arg Tyr Val  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe Cys  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 Leu Glu Thr His Glu Arg Phe Asn Pro Ile Val Asn Lys Thr Glu Ile  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 Glu Asn Val Arg Asn Gly Thr Gln Val Arg Tyr Tyr Arg Glu Ala Glu  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 Thr Glu Ala Phe Leu Thr Tyr Ile Glu Gly Val Cys Val Val Trp Phe  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 Thr Phe Glu Phe Leu Met Arg Val Val Phe Cys Pro Asn Lys Val Glu  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 Phe Ile Lys Asn Ser Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 Ile Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr His Phe  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 Lys Gln Lys Leu Pro Lys Lys Lys Lys Lys His Ile Pro Arg Pro Pro  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 Gln Leu Gly Ser Pro Asn Tyr Cys Lys Ser Val Val Asn Ser Pro His  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 His Ser Thr Gln Ser Asp Thr Cys Pro Leu Ala Gln Glu Glu Ile Leu  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 Glu Ile Asn Arg Ala Asp Ser Lys Leu Asn Gly Glu Val Ala Lys Ala  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 Ala Leu Ala Asn Glu Asp Cys Pro His Ile Asp Gln Ala Leu Thr Pro  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 Asp Glu Gly Leu Pro Phe Thr Arg Ser Gly Thr Arg Glu Arg Tyr Gly  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 Pro Cys Phe Leu Leu Ser Thr Gly Glu Tyr Ala Cys Pro Pro Gly Gly  
               
               
                 545                 550                 555                 560  
               
               
                   
               
               
                 Gly Met Arg Lys Asp Leu Cys Lys Glu Ser Pro Val Ile Ala Lys Tyr  
               
               
                                 565                 570                 575  
               
               
                   
               
               
                 Met Pro Thr Glu Ala Val Arg Val Thr  
               
               
                             580                 585  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 3  
               
               
                 &lt;211&gt; LENGTH: 2441  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: gene  
               
               
                 &lt;222&gt; LOCATION: (1)..(2411)  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: CDS  
               
               
                 &lt;222&gt; LOCATION: (37)..(1953)  
               
               
                 &lt;300&gt; PUBLICATION INFORMATION:  
               
               
                 &lt;301&gt; AUTHORS: McCormack,T., Vega-Saenz de Miera,E.C. and Rudy,B.  
               
               
                 &lt;302&gt; TITLE: Molecular cloning of a member of a third class of  
               
               
                       Shaker-family K+channel genes in mammals  
               
               
                 &lt;303&gt; JOURNAL: Proc. Natl. Acad. Sci. U.S.A.  
               
               
                 &lt;304&gt; VOLUME: 88  
               
               
                 &lt;305&gt; ISSUE: 9  
               
               
                 &lt;308&gt; DATABASE ACCESSION NUMBER: NM_139217  
               
               
                 &lt;309&gt; DATABASE ENTRY DATE: 1991-05-01  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 3  
               
               
                   
               
               
                 gtgttcgcct tccctagtca tgtctgagcc acagag atg ggc aag atc gag aac       54  
               
               
                                                         Met Gly Lys Ile Glu Asn  
               
               
                                                         1               5  
               
               
                   
               
               
                 aac gag agg gtg atc ctc aat gtc gga ggc acc agg cac gaa acc tac      102  
               
               
                 Asn Glu Arg Val Ile Leu Asn Val Gly Gly Thr Arg His Glu Thr Tyr  
               
               
                             10                  15                  20  
               
               
                   
               
               
                 cgc agc act ctc aag acc ctt cct gga act cgc ctg gcc ctt ctc gcc      150  
               
               
                 Arg Ser Thr Leu Lys Thr Leu Pro Gly Thr Arg Leu Ala Leu Leu Ala  
               
               
                         25                  30                  35  
               
               
                   
               
               
                 tcc tct gaa cct cag ggc gac tgc ctg act gct gcg ggt gac aag ctg      198  
               
               
                 Ser Ser Glu Pro Gln Gly Asp Cys Leu Thr Ala Ala Gly Asp Lys Leu  
               
               
                     40                  45                  50  
               
               
                   
               
               
                 cag ccg ctg ccc cct ccg ctg tct cca ccg ccg cga ccg cct ccc ttg      246  
               
               
                 Gln Pro Leu Pro Pro Pro Leu Ser Pro Pro Pro Arg Pro Pro Pro Leu  
               
               
                 55                  60                  65                  70  
               
               
                   
               
               
                 tcc cct gtc ccc agc ggc tgc ttc gag ggc ggc gca ggc aac tgc agt      294  
               
               
                 Ser Pro Val Pro Ser Gly Cys Phe Glu Gly Gly Ala Gly Asn Cys Ser  
               
               
                                 75                  80                  85  
               
               
                   
               
               
                 tcg cac ggt ggc aat ggc agc gac cac cct ggg gga ggc cgc gaa ttc      342  
               
               
                 Ser His Gly Gly Asn Gly Ser Asp His Pro Gly Gly Gly Arg Glu Phe  
               
               
                             90                  95                  100  
               
               
                   
               
               
                 ttc ttc gat cgc cac cca gga gtc ttc gcc tat gtg ctc aac tac tac      390  
               
               
                 Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn Tyr Tyr  
               
               
                         105                 110                 115  
               
               
                   
               
               
                 cgc acg ggc aag ctg cac tgc ccc gcc gac gtg tgt gga ccg ctc ttc      438  
               
               
                 Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe  
               
               
                     120                 125                 130  
               
               
                   
               
               
                 gag gaa gag ctg gca ttc tgg ggc atc gat gag acc gac gtg gag ccc      486  
               
               
                 Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro  
               
               
                 135                 140                 145                 150  
               
               
                   
               
               
                 tgc tgc tgg atg acc tac agg cag cac cgg gac gcg gag gag gcc ctg      534  
               
               
                 Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu  
               
               
                                 155                 160                 165  
               
               
                   
               
               
                 gat atc ttc gag aca ccc gac ctc atc gga ggc gac cct ggt gat gat      582  
               
               
                 Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro Gly Asp Asp  
               
               
                             170                 175                 180  
               
               
                   
               
               
                 gag gac cta ggg ggc aag aga ctg ggc att gag gat gct gcg ggg ctg      630  
               
               
                 Glu Asp Leu Gly Gly Lys Arg Leu Gly Ile Glu Asp Ala Ala Gly Leu  
               
               
                         185                 190                 195  
               
               
                   
               
               
                 gga gga ccc gat ggc aag tct ggc cgc tgg agg aag ctg cag cct cgc      678  
               
               
                 Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp Arg Lys Leu Gln Pro Arg  
               
               
                     200                 205                 210  
               
               
                   
               
               
                 atg tgg gct ctc ttt gag gac ccc tat tca tcc aga gcc gct agg ttt      726  
               
               
                 Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe  
               
               
                 215                 220                 225                 230  
               
               
                   
               
               
                 att gct ttt gct tct ctg ttc ttc att ttg gtt tcc atc aca acc ttt      774  
               
               
                 Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser Ile Thr Thr Phe  
               
               
                                 235                 240                 245  
               
               
                   
               
               
                 tgc ctg gag aca cac gaa gct ttc aat att gtt aaa aac aag aca gag      822  
               
               
                 Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu  
               
               
                             250                 255                 260  
               
               
                   
               
               
                 cca gtc atc aac ggc acc agc gct gtt ctc cag tat gaa atc gaa acg      870  
               
               
                 Pro Val Ile Asn Gly Thr Ser Ala Val Leu Gln Tyr Glu Ile Glu Thr  
               
               
                         265                 270                 275  
               
               
                   
               
               
                 gat cct gcc ttg aca tat gtg gaa gga gtg tgt gtg gtg tgg ttt act      918  
               
               
                 Asp Pro Ala Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr  
               
               
                     280                 285                 290  
               
               
                   
               
               
                 ttt gaa ttt tta gtc cgt att gtt ttc tcg ccc aat aaa ctt gag ttc      966  
               
               
                 Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu Glu Phe  
               
               
                 295                 300                 305                 310  
               
               
                   
               
               
                 atc aaa aat cta ttg aac atc att gac ttt gtg gcc atc ctc ccc ttc     1014  
               
               
                 Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro Phe  
               
               
                                 315                 320                 325  
               
               
                   
               
               
                 tac tta gag gtg gga ctc agc ggg ctg tct tcc aaa gcg gct aaa gat     1062  
               
               
                 Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala Ala Lys Asp  
               
               
                             330                 335                 340  
               
               
                   
               
               
                 gtg ctc ggc ttt ctc agg gtg gtt agg ttt gtg agg atc ctg aga atc     1110  
               
               
                 Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg Ile  
               
               
                         345                 350                 355  
               
               
                   
               
               
                 ttc aag ctt acc cgc cat ttc gta ggt ctg aga gtg ctc gga cac act     1158  
               
               
                 Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His Thr  
               
               
                     360                 365                 370  
               
               
                   
               
               
                 ctt cgt gcg agc acc aat gaa ttt ttg ttg ctg atc atc ttt ctg gct     1206  
               
               
                 Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala  
               
               
                 375                 380                 385                 390  
               
               
                   
               
               
                 ctg gga gtt ttg ata ttc gct acg atg atc tac tac gct gag cga gta     1254  
               
               
                 Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg Val  
               
               
                                 395                 400                 405  
               
               
                   
               
               
                 ggg gct caa cct aat gat ccc tca gcg agt gag cac aca cag ttc aaa     1302  
               
               
                 Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr Gln Phe Lys  
               
               
                             410                 415                 420  
               
               
                   
               
               
                 aac atc ccc att ggt ttc tgg tgg gct gtg gtg acc atg act acc tta     1350  
               
               
                 Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr Leu  
               
               
                         425                 430                 435  
               
               
                   
               
               
                 ggc tat ggg gat atg tac ccc caa aca tgg tca ggg atg ttg gtg ggg     1398  
               
               
                 Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly  
               
               
                     440                 445                 450  
               
               
                   
               
               
                 gcc ttg tgt gct ctg gct gga gtg ctg acc ata gct atg cct gtg ccc     1446  
               
               
                 Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val Pro  
               
               
                 455                 460                 465                 470  
               
               
                   
               
               
                 gtc att gtc aac aat ttt ggg atg tac tac tcc ttg gca atg gcg aag     1494  
               
               
                 Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala Lys  
               
               
                                 475                 480                 485  
               
               
                   
               
               
                 cag aaa ctt cca aga aaa aga aag aag cac att cct cct gcc cct ctg     1542  
               
               
                 Gln Lys Leu Pro Arg Lys Arg Lys Lys His Ile Pro Pro Ala Pro Leu  
               
               
                             490                 495                 500  
               
               
                   
               
               
                 gca agc tca cct aca ttt tgc aag aca gaa tta aac atg gct tgt aac     1590  
               
               
                 Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met Ala Cys Asn  
               
               
                         505                 510                 515  
               
               
                   
               
               
                 agt acc cag agt gac aca tgt ctg ggc aaa gaa aac cgg ctt ctg gaa     1638  
               
               
                 Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Glu Asn Arg Leu Leu Glu  
               
               
                     520                 525                 530  
               
               
                   
               
               
                 cat aac aga tca gtg tta tca ggt gac gac agt aca gga agt gag ccg     1686  
               
               
                 His Asn Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro  
               
               
                 535                 540                 545                 550  
               
               
                   
               
               
                 cca tta tca cct ccg gaa agg ctc ccc atc aga cgc tct agt acc aga     1734  
               
               
                 Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser Thr Arg  
               
               
                                 555                 560                 565  
               
               
                   
               
               
                 gac aaa aac aga aga ggg gaa aca tgt ttc ctg ttg acg aca ggt gat     1782  
               
               
                 Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp  
               
               
                             570                 575                 580  
               
               
                   
               
               
                 tac acg tgc gct tct gat gga gga atc agg aaa gga tat gaa aaa tcc     1830  
               
               
                 Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu Lys Ser  
               
               
                         585                 590                 595  
               
               
                   
               
               
                 cga agc tta aac aac ata gcg ggc ttg gca ggc aat gct ctg aga ctc     1878  
               
               
                 Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu  
               
               
                     600                 605                 610  
               
               
                   
               
               
                 tct cca gta aca tcc ccc tac aac tct ccg tgt cct ctg agg cgc tct     1926  
               
               
                 Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser  
               
               
                 615                 620                 625                 630  
               
               
                   
               
               
                 cgg tct ccc atc cca tct atc ttg taa accaaactgc accaatcggc           1973  
               
               
                 Arg Ser Pro Ile Pro Ser Ile Leu  
               
               
                                 635  
               
               
                   
               
               
                 taaattctat cactacaact cctgtccacc ctgtactgga aacaattaac tatagagttt   2033  
               
               
                   
               
               
                 ctccaggctc cattaagaac agtgtagatc ctgcatgaca ttactattcg aagtcagaaa   2093  
               
               
                   
               
               
                 tgctactcga gtagctagaa catcttttcc tggctttaaa gatggcctaa agtagtgctg   2153  
               
               
                   
               
               
                 ctactcagta agagttgccc aatttccttt cgctatacgg tgaccaatag cgtcagatat   2213  
               
               
                   
               
               
                 tggccagtgc acgaatgcat aagcaaatct tcagggagat attctttaat agtgtgcttc   2273  
               
               
                   
               
               
                 taaatgccaa ccacttcact ggaccttcct ttcttgtgac tgactccaac ccattctgaa   2333  
               
               
                   
               
               
                 gatgtctggg atcctatcta gatcgtataa accatgactt tggtcagctc gtttgcatgg   2393  
               
               
                   
               
               
                 accatcttgc ctgtatcacc tgaatacagt gtgtagcgtc ctggtacc                2441  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 4  
               
               
                 &lt;211&gt; LENGTH: 638  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 4  
               
               
                   
               
               
                 Met Gly Lys Ile Glu Asn Asn Glu Arg Val Ile Leu Asn Val Gly Gly  
               
               
                 1               5                   10                  15  
               
               
                   
               
               
                 Thr Arg His Glu Thr Tyr Arg Ser Thr Leu Lys Thr Leu Pro Gly Thr  
               
               
                             20                  25                  30  
               
               
                   
               
               
                 Arg Leu Ala Leu Leu Ala Ser Ser Glu Pro Gln Gly Asp Cys Leu Thr  
               
               
                         35                  40                  45  
               
               
                   
               
               
                 Ala Ala Gly Asp Lys Leu Gln Pro Leu Pro Pro Pro Leu Ser Pro Pro  
               
               
                     50                  55                  60  
               
               
                   
               
               
                 Pro Arg Pro Pro Pro Leu Ser Pro Val Pro Ser Gly Cys Phe Glu Gly  
               
               
                 65                  70                  75                  80  
               
               
                   
               
               
                 Gly Ala Gly Asn Cys Ser Ser His Gly Gly Asn Gly Ser Asp His Pro  
               
               
                                 85                  90                  95  
               
               
                   
               
               
                 Gly Gly Gly Arg Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 Tyr Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 Glu Thr Asp Val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His Arg  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 Asp Ala Glu Glu Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 Gly Asp Pro Gly Asp Asp Glu Asp Leu Gly Gly Lys Arg Leu Gly Ile  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 Glu Asp Ala Ala Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 Arg Lys Leu Gln Pro Arg Met Trp Ala Leu Phe Glu Asp Pro Tyr Ser  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 Ser Arg Ala Ala Arg Phe Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 Val Ser Ile Thr Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 Val Lys Asn Lys Thr Glu Pro Val Ile Asn Gly Thr Ser Ala Val Leu  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 Gln Tyr Glu Ile Glu Thr Asp Pro Ala Leu Thr Tyr Val Glu Gly Val  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 Cys Val Val Trp Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 Pro Asn Lys Leu Glu Phe Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 Tyr Tyr Ala Glu Arg Val Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 Glu His Thr Gln Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Arg Lys Arg Lys Lys His  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 Ile Pro Pro Ala Pro Leu Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 Leu Asn Met Ala Cys Asn Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 Glu Asn Arg Leu Leu Glu His Asn Arg Ser Val Leu Ser Gly Asp Asp  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 Ser Thr Gly Ser Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile  
               
               
                 545                 550                 555                 560  
               
               
                   
               
               
                 Arg Arg Ser Ser Thr Arg Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe  
               
               
                                 565                 570                 575  
               
               
                   
               
               
                 Leu Leu Thr Thr Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg  
               
               
                             580                 585                 590  
               
               
                   
               
               
                 Lys Gly Tyr Glu Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala  
               
               
                         595                 600                 605  
               
               
                   
               
               
                 Gly Asn Ala Leu Arg Leu Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro  
               
               
                     610                 615                 620  
               
               
                   
               
               
                 Cys Pro Leu Arg Arg Ser Arg Ser Pro Ile Pro Ser Ile Leu  
               
               
                 625                 630                 635  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 5  
               
               
                 &lt;211&gt; LENGTH: 3410  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: CDS  
               
               
                 &lt;222&gt; LOCATION: (223)..(2262)  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: gene  
               
               
                 &lt;222&gt; LOCATION: (1)..(3410)  
               
               
                 &lt;300&gt; PUBLICATION INFORMATION:  
               
               
                 &lt;301&gt; AUTHORS: Vega-Saenz de Miera,E., Moreno,H., Fruhling,D., Kentros,  
               
               
                       C. and Rudy,B.  
               
               
                 &lt;302&gt; TITLE: Cloning of ShIII (Shaw-like) cDNAs encoding a novel  
               
               
                       high-voltage-activating, TEA-sensitive, type-A K+ channel  
               
               
                 &lt;303&gt; JOURNAL: Proc. R. Soc. Lond., B, Biol. Sci.  
               
               
                 &lt;304&gt; VOLUME: 248  
               
               
                 &lt;305&gt; ISSUE: 1321  
               
               
                 &lt;306&gt; PAGES: 9-18  
               
               
                 &lt;308&gt; DATABASE ACCESSION NUMBER: NM_053997  
               
               
                 &lt;309&gt; DATABASE ENTRY DATE: 1991-05-01  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 5  
               
               
                   
               
               
                 aagctttttg tgcaatccca cctcctctag ctaggcttgg ttagagtctg cctagccgtg     60  
               
               
                   
               
               
                 gccccgccca ctccatcagt ccaatcagct cgtgttctcc ctccacctgc ccaatcactc    120  
               
               
                   
               
               
                 cctccccatc cattcatcgc ctcctcctgc ccaatcacat ctgcttctct accaaggctc    180  
               
               
                   
               
               
                 cgccccaaca ccctgccccc ctcagccccg cctccctgtc ca atg ctc agc tca       234  
               
               
                                                                Met Leu Ser Ser  
               
               
                                                                1  
               
               
                   
               
               
                 gtg tgc gtc tgg tcg ttc agc ggg cgc cag ggg acc cgc aag cag cat      282  
               
               
                 Val Cys Val Trp Ser Phe Ser Gly Arg Gln Gly Thr Arg Lys Gln His  
               
               
                 5                   10                  15                  20  
               
               
                   
               
               
                 tct cag ccg gcg cca acg ccg cag ccg cct gag tcc tca ccg ccg cct      330  
               
               
                 Ser Gln Pro Ala Pro Thr Pro Gln Pro Pro Glu Ser Ser Pro Pro Pro  
               
               
                                 25                  30                  35  
               
               
                   
               
               
                 ctg cta ccg ccg ccg cag cag cag tgc gct cag ccc ggc acc gcc gcc      378  
               
               
                 Leu Leu Pro Pro Pro Gln Gln Gln Cys Ala Gln Pro Gly Thr Ala Ala  
               
               
                             40                  45                  50  
               
               
                   
               
               
                 tcc ccg gcg ggt gcc ccg ctt tcc tgt ggg cct ggg ggc cgg cgc gcc      426  
               
               
                 Ser Pro Ala Gly Ala Pro Leu Ser Cys Gly Pro Gly Gly Arg Arg Ala  
               
               
                         55                  60                  65  
               
               
                   
               
               
                 gag cca tgc tcc ggg ctg ccg gcg gtg gcc atg ggg cgg cac ggc ggc      474  
               
               
                 Glu Pro Cys Ser Gly Leu Pro Ala Val Ala Met Gly Arg His Gly Gly  
               
               
                     70                  75                  80  
               
               
                   
               
               
                 ggc ggc ggc gac agc ggt aag atc gtg atc aac gtg ggc ggc gtg cgc      522  
               
               
                 Gly Gly Gly Asp Ser Gly Lys Ile Val Ile Asn Val Gly Gly Val Arg  
               
               
                 85                  90                  95                  100  
               
               
                   
               
               
                 cat gag acg tac cgc tcc acg ttg cgc acc cta ccg ggg acc cgg ctg      570  
               
               
                 His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro Gly Thr Arg Leu  
               
               
                                 105                 110                 115  
               
               
                   
               
               
                 gcc ggg ctg acc gag ccc gag gcg gcc gcg cgc ttt gac tac gac ccg      618  
               
               
                 Ala Gly Leu Thr Glu Pro Glu Ala Ala Ala Arg Phe Asp Tyr Asp Pro  
               
               
                             120                 125                 130  
               
               
                   
               
               
                 ggc acg gac gag ttc ttc ttt gac cgt cac ccg ggc gtc ttc gcc tac      666  
               
               
                 Gly Thr Asp Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr  
               
               
                         135                 140                 145  
               
               
                   
               
               
                 gtg ctc aac tac tac cgc acc ggc aag ctg cac tgc ccg gcc gac gtg      714  
               
               
                 Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys Pro Ala Asp Val  
               
               
                     150                 155                 160  
               
               
                   
               
               
                 tgc ggg ccg ctc ttc gag gag gag ctg ggc ttc tgg ggc ata gac gag      762  
               
               
                 Cys Gly Pro Leu Phe Glu Glu Glu Leu Gly Phe Trp Gly Ile Asp Glu  
               
               
                 165                 170                 175                 180  
               
               
                   
               
               
                 acg gac gtg gag gcc tgc tgc tgg atg acc tac cgc cag cac cgt gat      810  
               
               
                 Thr Asp Val Glu Ala Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp  
               
               
                                 185                 190                 195  
               
               
                   
               
               
                 gcc gaa gag gca ctg gac tcc ttc gag gct ccg gac tcc tcg ggc aac      858  
               
               
                 Ala Glu Glu Ala Leu Asp Ser Phe Glu Ala Pro Asp Ser Ser Gly Asn  
               
               
                             200                 205                 210  
               
               
                   
               
               
                 gcc aac gcc aac gcc gga ggc gcc cat gat gcg ggc ctg gac gac gag      906  
               
               
                 Ala Asn Ala Asn Ala Gly Gly Ala His Asp Ala Gly Leu Asp Asp Glu  
               
               
                         215                 220                 225  
               
               
                   
               
               
                 gcg ggc gca gga ggt ggc ggc ctg gac ggg gca ggc ggc gag ctc aag      954  
               
               
                 Ala Gly Ala Gly Gly Gly Gly Leu Asp Gly Ala Gly Gly Glu Leu Lys  
               
               
                     230                 235                 240  
               
               
                   
               
               
                 cgt ctg tgt ttt cag gac gcg ggc gga ggt gcc gga gga cct gcc gga     1002  
               
               
                 Arg Leu Cys Phe Gln Asp Ala Gly Gly Gly Ala Gly Gly Pro Ala Gly  
               
               
                 245                 250                 255                 260  
               
               
                   
               
               
                 ggc ccg ggc ggc gcg ggc ggc acg tgg tgg agg cgc tgg cag ccc cgc     1050  
               
               
                 Gly Pro Gly Gly Ala Gly Gly Thr Trp Trp Arg Arg Trp Gln Pro Arg  
               
               
                                 265                 270                 275  
               
               
                   
               
               
                 gtg tgg gcg ctt ttt gag gac ccc tac tcg tcg cgg gcc gcc agg tac     1098  
               
               
                 Val Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg Ala Ala Arg Tyr  
               
               
                             280                 285                 290  
               
               
                   
               
               
                 gtg gcc ttc gcc tcc cta ttc ttt atc ctc atc tcc atc acc acc ttc     1146  
               
               
                 Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Ile Ser Ile Thr Thr Phe  
               
               
                         295                 300                 305  
               
               
                   
               
               
                 tgc ctg gag aca cac gag ggc ttc atc cac atc agc aac aag acg gtg     1194  
               
               
                 Cys Leu Glu Thr His Glu Gly Phe Ile His Ile Ser Asn Lys Thr Val  
               
               
                     310                 315                 320  
               
               
                   
               
               
                 acg cag gcc tct cca atc cct ggg gct ccc ccg gag aat atc acc aat     1242  
               
               
                 Thr Gln Ala Ser Pro Ile Pro Gly Ala Pro Pro Glu Asn Ile Thr Asn  
               
               
                 325                 330                 335                 340  
               
               
                   
               
               
                 gtg gag gtg gag acg gaa ccc ttt ttg acc tac gtg gaa ggc gtg tgt     1290  
               
               
                 Val Glu Val Glu Thr Glu Pro Phe Leu Thr Tyr Val Glu Gly Val Cys  
               
               
                                 345                 350                 355  
               
               
                   
               
               
                 gtg gtc tgg ttc acc ttt gag ttt ctc atg cgg gtc acc ttc tgc ccg     1338  
               
               
                 Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val Thr Phe Cys Pro  
               
               
                             360                 365                 370  
               
               
                   
               
               
                 gat aag gtg gag ttt ctc aaa agc agt ctt aac atc atc gac tgt gta     1386  
               
               
                 Asp Lys Val Glu Phe Leu Lys Ser Ser Leu Asn Ile Ile Asp Cys Val  
               
               
                         375                 380                 385  
               
               
                   
               
               
                 gcc atc ttg ccc ttc tac ttg gaa gtg ggc ctg tca ggt ctc agc tcc     1434  
               
               
                 Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser  
               
               
                     390                 395                 400  
               
               
                   
               
               
                 aaa gct gcc aag gac gtg ctg ggc ttc ctg cgc gtc gtc cgc ttc gtg     1482  
               
               
                 Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val  
               
               
                 405                 410                 415                 420  
               
               
                   
               
               
                 cgc atc ctc cgt atc ttc aag ctg acc cgc cat ttt gtg ggc ctg cgg     1530  
               
               
                 Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg  
               
               
                                 425                 430                 435  
               
               
                   
               
               
                 gtc ctg ggc cac acg ctc cgt gcc agc acc aac gag ttc ttg tta ctc     1578  
               
               
                 Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu  
               
               
                             440                 445                 450  
               
               
                   
               
               
                 att att ttc ctg gct ctg ggg gtc ctc atc ttt gcc acc atg atc tac     1626  
               
               
                 Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr  
               
               
                         455                 460                 465  
               
               
                   
               
               
                 tat gcc gag cgc atc ggg gcc gat cct gat gac atc ctg ggc tcc aac     1674  
               
               
                 Tyr Ala Glu Arg Ile Gly Ala Asp Pro Asp Asp Ile Leu Gly Ser Asn  
               
               
                     470                 475                 480  
               
               
                   
               
               
                 cac acc tac ttc aag aac atc ccc atc ggc ttc tgg tgg gct gtg gtc     1722  
               
               
                 His Thr Tyr Phe Lys Asn Ile Pro Ile Gly Phe Trp Trp Ala Val Val  
               
               
                 485                 490                 495                 500  
               
               
                   
               
               
                 acc atg acc aca ctg ggc tat ggt gac atg tac ccc aag aca tgg tct     1770  
               
               
                 Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Lys Thr Trp Ser  
               
               
                                 505                 510                 515  
               
               
                   
               
               
                 ggg atg ctg gtc ggg gca ctg tgt gcc ctg gct ggt gtg ctg acc att     1818  
               
               
                 Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile  
               
               
                             520                 525                 530  
               
               
                   
               
               
                 gcc atg ccg gtg ccc gtc att gtc aac aac ttc ggc atg tac tat tca     1866  
               
               
                 Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser  
               
               
                         535                 540                 545  
               
               
                   
               
               
                 ctg gct atg gcc aag cag aaa ttg cca aag aag aaa aac aaa cat atc     1914  
               
               
                 Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys Asn Lys His Ile  
               
               
                     550                 555                 560  
               
               
                   
               
               
                 ccc agg ccc ccg cag cct ggc tca ccc aac tac tgc aag ccc gat ccc     1962  
               
               
                 Pro Arg Pro Pro Gln Pro Gly Ser Pro Asn Tyr Cys Lys Pro Asp Pro  
               
               
                 565                 570                 575                 580  
               
               
                   
               
               
                 ccg cct ccg ccc cca cca cac ccc cac cac ggc agc ggt ggc atc agc     2010  
               
               
                 Pro Pro Pro Pro Pro Pro His Pro His His Gly Ser Gly Gly Ile Ser  
               
               
                                 585                 590                 595  
               
               
                   
               
               
                 cca cca ccg ccc atc acc cct cct tcc atg ggg gtg act gtg gct ggg     2058  
               
               
                 Pro Pro Pro Pro Ile Thr Pro Pro Ser Met Gly Val Thr Val Ala Gly  
               
               
                             600                 605                 610  
               
               
                   
               
               
                 gct tac cca cct gga ccc cac acg cac ccc ggg ctg ctt agg ggt ggt     2106  
               
               
                 Ala Tyr Pro Pro Gly Pro His Thr His Pro Gly Leu Leu Arg Gly Gly  
               
               
                         615                 620                 625  
               
               
                   
               
               
                 gct ggg gga ctg gga att atg gga ttg cct cct ctg cca gcc cct ggt     2154  
               
               
                 Ala Gly Gly Leu Gly Ile Met Gly Leu Pro Pro Leu Pro Ala Pro Gly  
               
               
                     630                 635                 640  
               
               
                   
               
               
                 gag ccc tgc cca ctg gct caa gaa gag gtg att gaa acc aac agg gca     2202  
               
               
                 Glu Pro Cys Pro Leu Ala Gln Glu Glu Val Ile Glu Thr Asn Arg Ala  
               
               
                 645                 650                 655                 660  
               
               
                   
               
               
                 ggt gag gct gga gcc agg act gga ggt gtg gga aga cct ggg ggt tgg     2250  
               
               
                 Gly Glu Ala Gly Ala Arg Thr Gly Gly Val Gly Arg Pro Gly Gly Trp  
               
               
                                 665                 670                 675  
               
               
                   
               
               
                 ggg tcg ggg tag ggggaggagg cggcagggtt ggaggggatg cagaggcagg         2302  
               
               
                 Gly Ser Gly  
               
               
                   
               
               
                 atttctctta ggttcaggct gagcagagtg gaaggcaaca gggcagacag aagggacaag   2362  
               
               
                   
               
               
                 tggctagaag gctggagagg aggcacaagg agccacagaa accggattcc gtgtacaaga   2422  
               
               
                   
               
               
                 gagtgtgtga acatggattt cagccaggct gctctgaaag gcccctggtc agaagcagca   2482  
               
               
                   
               
               
                 cagtgagggt ctttggagaa gagactcaga aacccaggtg tgatggtgca tgcctccctt   2542  
               
               
                   
               
               
                 cctttgaagg tacttggtac ctcacatact tgggagatag aagtaggagg atgacgagtt   2602  
               
               
                   
               
               
                 caaggctagc ctgggtgaca tgtccctgtc tcaaaaatca tgggagaaaa aaatgaaaga   2662  
               
               
                   
               
               
                 gaaagaaagg aaagaggttg ggaggggtag gggagaaaga gaaaggcttg gtggcactct   2722  
               
               
                   
               
               
                 cctatagttc caacactggg gagactgagg caggagggtc aacacgtgtt ttgaggctat   2782  
               
               
                   
               
               
                 cctgggctac atacacagaa acaaaaggtc tgagtagctt cctgggggct gctagttcac   2842  
               
               
                   
               
               
                 accgattctt agggatattc ctatttctct atgagaaggc aagggaagac agggagagat   2902  
               
               
                   
               
               
                 agaaaggaaa aagggaaagg aatgagagcc acgtatggta atcctaaaat ggaggaggat   2962  
               
               
                   
               
               
                 caggagttca aggccggtgt cagctacgtg agaccctgtc tcagaaagaa aggggctcct   3022  
               
               
                   
               
               
                 gtaaagcaca ggaagtcgcg cgtgactcct ggcaaggcta gaggcaggtc tggctactgt   3082  
               
               
                   
               
               
                 cactttgtga ctgtggccgg tagtcctgag agccagagct ggggaatgta agtcacttaa   3142  
               
               
                   
               
               
                 ggagagaggg agaatggagt caggctgcca ggagggtcga ggtggaccct cgtaaaggaa   3202  
               
               
                   
               
               
                 ggcaaaaggg aggaacagac caaggccagc atcagggtgc ggagctgcca ggcagggtct   3262  
               
               
                   
               
               
                 gcacagggca gcaggaggca ctagggatcc cagagagttc ttgtaagaga agaggcagcc   3322  
               
               
                   
               
               
                 aggactggtt gaacgtacct gttatcccag gatttgggaa gctgaggcag aaggacagtt   3382  
               
               
                   
               
               
                 aagttcagag ctagcctgga ctatagag                                      3410  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 6  
               
               
                 &lt;211&gt; LENGTH: 679  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Rattus norvegicus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 6  
               
               
                   
               
               
                 Met Leu Ser Ser Val Cys Val Trp Ser Phe Ser Gly Arg Gln Gly Thr  
               
               
                 1               5                   10                  15  
               
               
                   
               
               
                 Arg Lys Gln His Ser Gln Pro Ala Pro Thr Pro Gln Pro Pro Glu Ser  
               
               
                             20                  25                  30  
               
               
                   
               
               
                 Ser Pro Pro Pro Leu Leu Pro Pro Pro Gln Gln Gln Cys Ala Gln Pro  
               
               
                         35                  40                  45  
               
               
                   
               
               
                 Gly Thr Ala Ala Ser Pro Ala Gly Ala Pro Leu Ser Cys Gly Pro Gly  
               
               
                     50                  55                  60  
               
               
                   
               
               
                 Gly Arg Arg Ala Glu Pro Cys Ser Gly Leu Pro Ala Val Ala Met Gly  
               
               
                 65                  70                  75                  80  
               
               
                   
               
               
                 Arg His Gly Gly Gly Gly Gly Asp Ser Gly Lys Ile Val Ile Asn Val  
               
               
                                 85                  90                  95  
               
               
                   
               
               
                 Gly Gly Val Arg His Glu Thr Tyr Arg Ser Thr Leu Arg Thr Leu Pro  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 Gly Thr Arg Leu Ala Gly Leu Thr Glu Pro Glu Ala Ala Ala Arg Phe  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 Asp Tyr Asp Pro Gly Thr Asp Glu Phe Phe Phe Asp Arg His Pro Gly  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 Val Phe Ala Tyr Val Leu Asn Tyr Tyr Arg Thr Gly Lys Leu His Cys  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Gly Phe Trp  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 Gly Ile Asp Glu Thr Asp Val Glu Ala Cys Cys Trp Met Thr Tyr Arg  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ser Phe Glu Ala Pro Asp  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 Ser Ser Gly Asn Ala Asn Ala Asn Ala Gly Gly Ala His Asp Ala Gly  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 Leu Asp Asp Glu Ala Gly Ala Gly Gly Gly Gly Leu Asp Gly Ala Gly  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 Gly Glu Leu Lys Arg Leu Cys Phe Gln Asp Ala Gly Gly Gly Ala Gly  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 Gly Pro Ala Gly Gly Pro Gly Gly Ala Gly Gly Thr Trp Trp Arg Arg  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 Trp Gln Pro Arg Val Trp Ala Leu Phe Glu Asp Pro Tyr Ser Ser Arg  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 Ala Ala Arg Tyr Val Ala Phe Ala Ser Leu Phe Phe Ile Leu Ile Ser  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 Ile Thr Thr Phe Cys Leu Glu Thr His Glu Gly Phe Ile His Ile Ser  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 Asn Lys Thr Val Thr Gln Ala Ser Pro Ile Pro Gly Ala Pro Pro Glu  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 Asn Ile Thr Asn Val Glu Val Glu Thr Glu Pro Phe Leu Thr Tyr Val  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Met Arg Val  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 Thr Phe Cys Pro Asp Lys Val Glu Phe Leu Lys Ser Ser Leu Asn Ile  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 Ile Asp Cys Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 Gly Leu Ser Ser Lys Ala Ala Lys Asp Val Leu Gly Phe Leu Arg Val  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 Val Arg Phe Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 Val Gly Leu Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 Thr Met Ile Tyr Tyr Ala Glu Arg Ile Gly Ala Asp Pro Asp Asp Ile  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 Leu Gly Ser Asn His Thr Tyr Phe Lys Asn Ile Pro Ile Gly Phe Trp  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 Lys Thr Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 Val Leu Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 Met Tyr Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Lys Lys Lys  
               
               
                 545                 550                 555                 560  
               
               
                   
               
               
                 Asn Lys His Ile Pro Arg Pro Pro Gln Pro Gly Ser Pro Asn Tyr Cys  
               
               
                                 565                 570                 575  
               
               
                   
               
               
                 Lys Pro Asp Pro Pro Pro Pro Pro Pro Pro His Pro His His Gly Ser  
               
               
                             580                 585                 590  
               
               
                   
               
               
                 Gly Gly Ile Ser Pro Pro Pro Pro Ile Thr Pro Pro Ser Met Gly Val  
               
               
                         595                 600                 605  
               
               
                   
               
               
                 Thr Val Ala Gly Ala Tyr Pro Pro Gly Pro His Thr His Pro Gly Leu  
               
               
                     610                 615                 620  
               
               
                   
               
               
                 Leu Arg Gly Gly Ala Gly Gly Leu Gly Ile Met Gly Leu Pro Pro Leu  
               
               
                 625                 630                 635                 640  
               
               
                   
               
               
                 Pro Ala Pro Gly Glu Pro Cys Pro Leu Ala Gln Glu Glu Val Ile Glu  
               
               
                                 645                 650                 655  
               
               
                   
               
               
                 Thr Asn Arg Ala Gly Glu Ala Gly Ala Arg Thr Gly Gly Val Gly Arg  
               
               
                             660                 665                 670  
               
               
                   
               
               
                 Pro Gly Gly Trp Gly Ser Gly  
               
               
                         675  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 7  
               
               
                 &lt;211&gt; LENGTH: 45  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: oligonucleotide (45mer) used for in situ  
               
               
                       hybridization for the Kv3.1 alpha-subunit mRNA  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 7  
               
               
                   
               
               
                 atagtcgaag tggctgtggg cgtccggctc cgccagccag gcaag                     45  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 8  
               
               
                 &lt;211&gt; LENGTH: 45  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: oligonucleotide (45mer) used for in situ  
               
               
                       hybridization for Kv3.2 mRNA  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 8  
               
               
                   
               
               
                 cacatcttta gccgctttgg aagacagccc gctgagtccc acctc                     45  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 9  
               
               
                 &lt;211&gt; LENGTH: 45  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: oligonucleotide (45mer) used for in situ  
               
               
                       hybridization for Kv3.3 mRNA  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 9  
               
               
                   
               
               
                 agaatgctgc ttgcgggtcc cctggcgccc gctgaacgac cagac                     45