bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel excitatoryConuspeptides define a new conotoxin superfamily
Authors: Jimenez Elsie C. , Shetty Reshma P. , Lirazan Marcelina , Rivier Jean , Walker Craig , Abogadie Fe C. , Yoshikami Doju , Cruz Lourdes J. , Olivera Baldomero M. 
Published: July 2010

AbstractA new class ofConuspeptides, the I‐superfamily of conotoxins, has been characterized using biochemical, electrophysiological and molecular genetic methods. Peptides in this superfamily have a novel pattern of eight Cys residues. Five peptides that elicited excitatory symptomatology, r11a, r11b, r11c, r11d and r11e, were purified fromConus radiatusvenom; four were tested on amphibian peripheral axons and shown to elicit repetitive action potentials, consistent with being members of the ‘lightning‐strike cabal’ of toxins that effect instant immobilization of fish prey. A parallel analysis ofConuscDNA clones revealed a new class of conotoxin genes that was particularly enriched (with 18 identified paralogues) in aConus radiatusvenom duct library; severalC. radiatusclones encoded the excitatory peptides directly characterized from venom. The remarkable diversity of related I‐superfamily peptides within a singleConusspecies is unprecedented. When combined with the excitatory effects observed on peripheral circuitry, this unexpected diversity suggests a corresponding molecular complexity of the targeted signaling components in peripheral axons; the I‐conotoxin superfamily should provide a rich lode of pharmacological tools for dissecting and understanding these. Thus, the I‐superfamily conotoxins promise to provide a significant new technology platform for dissecting the molecular components of axons.
Changes in dialysate concentrations of glutamate and GABA in the brain: an index of volume transmission mediated actions?
Authors: Del Arco A. , Segovia G. , Fuxe K. , Mora F. 
Published: July 2010

AbstractBrain microdialysis has become a frequently used method to study the extracellular concentrations of neurotransmitters in specific areas of the brain. For years, and this is still the case today, dialysate concentrations and hence extracellular concentrations of neurotransmitters have been interpreted as a direct index of the neuronal release of these specific neurotransmitter systems. Although this seems to be the case for neurotransmitters such as dopamine, serotonin and acetylcholine, the extracellular concentrations of glutamate and GABA do not provide a reliable index of their synaptic exocytotic release. However, many microdialysis studies show changes in extracellular concentrations of glutamate and GABA under specific pharmacological and behavioural stimuli that could be interpreted as a consequence of the activation of specific neurochemical circuits. Despite this, we still do not know the origin and physiological significance of these changes of glutamate and GABA in the extracellular space. Here we propose that the changes in dialysate concentrations of these two neurotransmitters found under specific treatments could be an expression of the activity of the neurone–astrocyte unit in specific circuits of the brain. It is further proposed that dialysate changes of glutamate and GABA could be used as an index of volume transmission mediated actions of these two neurotransmitters in the brain. This hypothesis is based firstly on the assumption that the activity of neurones is functionally linked to the activity of astrocytes, which can release glutamate and GABA to the extracellular space; secondly, on the existence of extrasynaptic glutamate and GABA receptors with functional properties different from those of GABA receptors located at the synapse; and thirdly, on the experimental evidence reporting specific electrophysiological and neurochemical effects of glutamate and GABA when their levels are increased in the extracellular space. According to this concept, glutamate and GABA, once released into the extracellular compartment, could diffuse and have long‐lasting effects modulating glutamatergic and/or GABAergic neurone‐astrocytic networks and their interactions with other neurotransmitter neurone networks in the same areas of the brain.
The cortical serotonin2Areceptor and the pathology of schizophrenia: a likely accomplice
Authors: Dean Brian 
Published: July 2010

AbstractA large body of evidence shows that there is a change in the density of cortical serotonin2Areceptors (5HT2AR) in post‐mortem CNS from subjects with schizophrenia. Furthermore, some antipsychotic drugs have also been shown to cause a decrease in the density of 5HT2AR in the rat CNS. Thus, it appeared possible that changes in this receptor in human post‐mortem CNS simply reflected an antipsychotic drug effect. However, a great deal of research on the 5HT2AR and schizophrenia now suggests that the changes in this receptor are complex and may be involved in both the pathology of the disorder and the effects of some antipsychotic drugs. Moreover, recent advances in basic research on the role of the 5HT2AR in the CNS add further support to the hypothesis that the receptor could be involved in the pathology of the illness. In particular, an argument will be developed that the changes in the 5HT2AR in schizophrenia are reflective of a real or perceived change in serotonergic tone and that this forms an important part of the pathology of the illness.
Valproic acid down‐regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase‐1 and ‐2 in rat brain
Authors: Bosetti Francesca , Weerasinghe Gayani R. , Rosenberger Thad A. , Rapoport Stanley I. 
Published: July 2010

AbstractSodium valproate, a mood stabilizer, when chronically administered to rats (200 mg/kg i.p. daily for 30 days) significantly reduced the brain protein levels of cyclooxygenase (COX)‐1 and COX‐2, without altering the mRNA levels of these enzymes. COX activity was decreased, as were the brain concentrations of 11‐dehydrothromboxane B2 and prostaglandin E2 (PGE2), metabolites of arachidonic acid (AA) produced via COX. In contrast, the brain protein level of 5‐lipoxygenase and the concentration of its AA metabolite leukotriene B4 were unchanged. In view of published evidence that lithium chloride administered chronically to rats, like chronic valproate, reduces AA turnover within brain phospholipids, and that lithium post‐transcriptionally down‐regulates COX‐2 but not COX‐1 protein level and enzyme activity, these observations suggest that mood stabilizers generally modulate the release and recycling of AA within brain phospholipids, and the conversion of AA via COX‐2 to PGE2 and related eicosanoids. If targeting this part of the ‘AA cascade’ accounts for their therapeutic action, non‐steroidal anti‐inflammatory drugs or selective COX‐2 inhibitors might prove effective in bipolar disorder.
Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS
Authors: Kawahara Yukio , Kwak Shin , Sun Hui , Ito Kyoko , Hashida Hideji , Aizawa Hitoshi , Jeong Seon‐Yong , Kanazawa Ichiro 
Published: July 2010

AbstractAMPA receptor‐mediated neurotoxicity is currently the most plausible hypothesis for the etiology of amyotrophic lateral sclerosis (ALS). The mechanism initiating this type of neuronal death is believed to be exaggerated Ca2+‐influx through AMPA receptors, which is critically determined by the presence or absence of the glutamate receptor subunit 2 (GluR2) in the assembly. We have provided the first quantitative measurements of the expression profile of AMPA receptor subunits mRNAs in human single neurons by means of quantitative RT–PCR with a laser microdissector. Among the AMPA subunits, GluR2 shared the vast majority throughout the neuronal subsets and tissues examined. Furthermore, both the expression level and the proportion of GluR2 mRNA in motoneurons were the lowest among all neuronal subsets examined, whereas those in motoneurons of ALS did not differ from the control group, implying that selective reduction of the GluR2 subunit cannot be a mechanism of AMPA receptor‐mediated neurotoxicity in ALS. However, the low relative abundance of GluR2 might provide spinal motoneurons with conditions that are easily affected by changes of AMPA receptor properties including deficient GluR2 mRNA editing in ALS.
The human prion octarepeat fragment prevents and reverses the inhibitory action of copper in the P2X4receptor without modifying the zinc action
Authors: Lorca Ramón A. , Chacón Marcelo , Barría María Inés , Inestrosa Nibaldo C. , Huidobro‐Toro J. Pablo 
Published: July 2010

AbstractHuman prion protein fragments (PrP60−67or PrP59−91) prevented and reversed the inhibition elicited by 5 µmcopper on the P2X4receptor expressed inXenopus laevisoocytes. A 60‐s pre‐application of 5 µmcopper caused a 69.2 ± 2.6% inhibition of the 10 µmadenosine triphosphate (ATP)‐evoked currents, an effect that was prevented by mixing 5 µmcopper with 0.01–10 µmof the PrP fragments 1‐min prior to application. This interaction was selective, as PrP59−91did not alter the facilitatory action of zinc. The EC50of PrP60−67and PrP59−91for the reduction of the copper inhibition were 4.6 ± 1 and 1.3 ± 0.4 µm, respectively. A synthetic PrP59−91variant in which all four His were replaced by Ala was inactive. However, the replacement of Trp in each of the four putative copper‐binding domains by Ala slightly decreased its potency. Furthermore, the application of 10 µmPrP59−91reversed the copper‐evoked inhibition, restoring the ATP concentration curve to the same level as the non‐inhibited state. Fragment 139–157 of βA4 amyloid precursor protein also prevented the action of copper; its EC50was 1.6 ± 0.1 µm; the metal chelator penicillamine was equipotent with PrP60−67, but carnosine was significantly less potent. Our findings highlight the role of PrP in copper homeostasis and hint at its possible role as a modulator of synapses regulated by this trace metal.
A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD+ depletion and ribosylation of 14‐3‐3γ
Authors: Satchell Margaret A. , Zhang Xiaopeng , Kochanek Patrick M. , Dixon C. Edward , Jenkins Larry W. , Melick John , Szabó Csaba , Clark Robert S. B. 
Published: July 2010

AbstractPoly(ADP‐ribose) polymerase‐1 (PARP‐1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD+). In this study, systemic administration of the PARP‐1 inhibitor 5‐iodo‐6‐amino‐1,2‐benzopyrone (INH2BP) after TBI preserved brain NAD+ levels and dose‐dependently reduced poly‐ADP‐ribosylation 24 h after injury. While moderate‐dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured‐ and sham‐mice receiving high‐dose INH2BP were unable to learn in the Morris‐water maze. Poly‐ADP‐ribosylated peptides identified using a proteomics approach yielded several proteins potentially associated with memory, including structural proteins (tubulin α and β, γ‐actin, and α‐internexin neuronal intermediate filament protein) and 14‐3‐3γ. Nuclear poly‐ADP‐ribosylation of 14‐3‐3γ was completely inhibited by the dose of INH2BP that produced profound memory disturbances. Thus, partial inhibition of poly‐ADP‐ribosylation preserves NAD+ and improves functional outcome after TBI, whereas more complete inhibition impairs spatial memory acquisition independent of injury, and is associated with ribosylation of 14‐3‐3γ.
Isofurans, but not F2‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease
Authors: Fessel Joshua P. , Hulette Christine , Powell Suzanne , Roberts L. Jackson , Zhang Jing 
Published: July 2010

AbstractF2‐isoprostanes (F2‐IsoPs) are well‐established sensitive and specific markers of oxidative stressin vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F2‐IsoPs, their formation is favored when oxygen tension is increasedin vitroorin vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F2‐IsoPs and IsoFs. In this study, we attempted to compare the levels of F2‐IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age‐matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F2‐IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F2‐IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age‐matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.
Characterization of two novel proteins, NgRH1 and NgRH2, structurally and biochemically homologous to the Nogo‐66 receptor
Authors: Pignot V. , Hein A. E. , Barske C. , Wiessner C. , Walmsley A. R. , Kaupmann K. , Mayeur H. , Sommer B. , Mir A. K. , Frentzel S. 
Published: July 2010

AbstractNogo‐66 receptor (NgR) has recently been identified as the neuronal receptor of the myelin‐associated proteins Nogo‐A, oligodendrocyte protein (OMgp) and myelin‐associated glycoprotein (MAG), and mediates inhibition of axonal regeneration both in vitro and in vivo. Through database searches, we have identified two novel proteins (NgRH1 and NgRH2) that turned out to be homologous in their primary structures, biochemical properties and expression patterns to NgR. Like NgR, the homologues contain eight leucine‐rich repeats (LRR) flanked by a leucine‐rich repeat C‐terminus (LRRCT) and a leucine‐rich repeat N‐terminus (LRRNT), and also have a C‐terminal GPI signal sequence. Northern blot analysis showed predominant expression of NgRH1 and NgRH2 mRNA in the brain. In situ hybridization and immunohistochemistry on rat brain slices revealed neuronal expression of the genes. NgRH1 and NgRH2 were detected on the cell surface of recombinant cell lines as N‐glycosylated GPI anchored proteins and, consistent with other GPI anchored proteins, were localized within the lipid rafts of cellular membranes. In addition, an N‐terminal proteolytic fragment of NgR comprising the majority of the ectodomain was found to be constitutively secreted from cells. Our data indicate that NgR, NgRH1 and NgRH2 constitute a novel receptor protein family, which may play related roles within the CNS.
Differential regulation of NF‐κB, SRE and CRE by dopamine D1 and D2 receptors in transfected NG108‐15 cells
Authors: Takeuchi Yusuke , Fukunaga Kohji 
Published: July 2010

AbstractTo investigate transcriptional regulation by dopamine receptors, we established NG108‐15 cells stably expressing D1R, D2LR and D2SR (NGD1R, NGD2LR and NGD2SR) and evaluated the effects of these receptors on NF‐κB, SRE and CRE activity using luciferase reporter constructs. Stimulation with quinpirole, a selective D2R agonist, increased NF‐κB and SRE activity but decreased CRE activity in both NGD2R cell lines. By contrast, stimulation with SKF 38393, a selective D1R agonist, decreased NF‐κB and SRE activity but increased CRE activity in NGD1R cells. Stimulation with forskolin and overexpression of constitutively active PKA suppressed NF‐κB activity, likely due to D1R stimulation. D2R stimulation activated ERK, and treatment with U1026, a selective MEK inhibitor, eliminated D2R‐induced NF‐κB activation. D2R stimulation also activated the neural cell adhesion molecule (NCAM) promoter, which includes a potential NF‐κB site. Furthermore, by transfecting constitutively active CaM KII and MEKK, and dominant negative p38 MAPK, we show that the NCAM promoter is positively regulated by CaM KII but negatively regulated by p38 MAPK. These results indicate that D2R‐induced NF‐κB activation through ERK may be involved in activation of the NCAM promoter, and additionally that other protein kinases such as CaM KII and p38 MAPK also regulate NCAM expression.
Characterization of P2X3, P2Y1and P2Y4receptors in cultured HEK293‐hP2X3cells and their inhibition by ethanol and trichloroethanol
Authors: Fischer Wolfgang , Wirkner Kerstin , Weber Marco , Eberts Christoph , Köles Laszlo , Reinhardt Robert , Franke Heike , Allgaier Clemens , Gillen Clemens , Illes Peter 
Published: July 2010

AbstractMembrane currents and changes in the intracellular Ca2+concentration ([Ca2+]i) were measured in HEK293 cells transfected with the human P2X3receptor (HEK293‐hP2X3). RT‐PCR and immunocytochemistry indicated the additional presence of endogenous P2Y1and to some extent P2Y4receptors. P2 receptor agonists induced inward currents in HEK293‐hP2X3cells with the rank order of potency α,β‐meATP ≈ ATP > ADP‐β‐S > UTP. A comparable rise in [Ca2+]iwas observed after the slow superfusion of ATP, ADP‐β‐S and UTP; α,β‐meATP was ineffective. These data, in conjunction with results obtained by using the P2 receptor antagonists TNP‐ATP, PPADS and MRS2179 indicate that the current response to α,β‐meATP is due to P2X3receptor activation, while the ATP‐induced rise in [Ca2+]iis evoked by P2Y1and P2Y4receptor activation. TCE depressed the α,β‐meATP current in a manner compatible with a non‐competitive antagonism. The ATP‐induced increase of [Ca2+]iwas much less sensitive to the inhibitory effect of TCE than the current response to α,β‐meATP. The present study indicates that in HEK293‐hP2X3cells, TCE, but not ethanol, potently inhibits ligand‐gated P2X3receptors and, in addition, moderately interferes with G protein‐coupled P2Y1and P2Y4receptors. Such an effect may be relevant for the interruption of pain transmission in dorsal root ganglion neurons following ingestion of chloral hydrate or trichloroethylene.
Contribution of bradykinin and nitric oxide to AT2receptor‐mediated differentiation in PC12 W cells
Authors: Zhao Yi , Biermann Torsten , Luther Claudia , Unger Thomas , Culman Juraj , Gohlke Peter 
Published: July 2010

AbstractWe investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase‐contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10−7 m) increased the outgrowth of medium and large neurites by mean ± SEM 20.2 ± 2.3 and 6.6 ± 1.4 compared with 1.66 ± 0.5 and 0.1 ± 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50–250% with angiotensin II at concentrations of 10−6–10−4 m. Both blockade of AT2receptors and of nitric oxide synthase markedly reduced angiotensin II‐induced neurite outgrowth and cyclic GMP production. In contrast, B2receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8‐bromo‐cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT‐5823 inhibited the neurite outgrowth induced by both angiotensin II and 8‐bromo‐cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide‐related and cyclic GMP‐dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT2receptor and further enhanced by bradykinin B2receptor blockade.
Alternative splicing in single cells dissected from complex tissues: separate expression of prepro‐tachykinin A mRNA splice variants in sensory neurones
Authors: Springer Jochen , McGregor Gerard P. , Fink Ludger , Fischer Axel 
Published: July 2010

AbstractTachykinins play an important role in peripheral inflammatory diseases and disorders of the CNS. Most members of the tachykinin family are generated by alternative post‐transcriptional splicing of the prepro‐tachykinin (PPT) A gene. Here, we examined the simultaneous expression of PPT‐A splice variants in individual neurones of the nodose ganglion. In extracts of ganglia, the expression of the four PPT‐A mRNA splice variants and their four encoded peptides was shown by RT–PCR and combined HPLC and radioimmunoassay respectively. In order to examine prepro‐tachykinin A expression in individual cells, single neurones were isolated from the ganglia using laser‐assisted microdissection and processed for RT–PCR. Some 31.9% of the neurones investigated expressed a specific PPT‐A transcript. Each individual neurone was found to express only a single splice variant. This is the first study to analyse the differential expression of PPT‐A splice variants at the single‐cell level. In view of the large number of alternatively spliced genes in the human genome and the resulting profound physiological effects, including several diseases, the technique described here is useful for isolating cells without possible confounding effects of dissociated neuronal cultures. For PPT‐A, the results indicate that alternative post‐transcriptional splicing determines the tachykinergic phenotype and may therefore have important functional implications.
Protein kinase A and protein kinase C signaling pathway interaction in phenylethanolamineN‐methyltransferase gene regulation
Authors: Tai T. C. , Wong Dona L. 
Published: July 2010

AbstractThe protein kinase A (PKA) and protein kinase C (PKC) signaling pathways appear to interact in regulating phenylethanolamineN‐methyltransferase (PNMT) promoter‐driven gene transcription in PC12 cells. Forskolin treatment of cells transfected with the rat PNMT promoter‐luciferase reporter gene construct pGL3RP893 increased promoter activity approximately two‐fold whereas phorbol‐12‐myristate‐13 acetate (PMA) treatment had no effect. However, simultaneous forskolin and PMA treatment synergistically activated the PNMT promoter approximately four‐fold, suggesting that PKC stimulation requires prior induction of the PKA pathway. Consistent with this possibility the adenylate cyclase inhibitor MDL12,330A, and the PKA inhibitor H‐89 prevented PNMT promoter stimulation by the combination of forskolin and PMA. PKA and PKC regulation seems to be mediated in part by Egr‐1 and Sp1 through their consensus elements in the PNMT promoter. Forskolin and PMA treatment of PC12 cells increased Egr‐1 protein and phosphorylated Egr‐1/DNA‐binding complex formation to the same extent but only increased phosphorylated Sp1/DNA binding complex formation without altering Sp1 protein levels. Mutation of the − 165 bp Egr‐1 and − 48 bp Sp1 sites, respectively, attenuated and abolished combined forskolin and PMA‐mediated promoter activation. PNMT promoter analysis further showed that synergistic stimulation by PKA and PKC involves DNA sequences between − 442 and − 392 bp, and potentially a GCM binding element lying within this region.