GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gatedchloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABAA receptor. At least 16 distinct subunits of GABAA receptors have been identified. Transcript variants utilizing three different alternative non-coding first exons have been described.[5]
Subunit selective ligandsedit
Recent research has produced several ligands which are moderately selective for GABAA receptors containing the α5 subunit. These have proved to be useful in investigating some of the side effects of benzodiazepine and nonbenzodiazepine drugs, particularly the effects on learning and memory such as anterograde amnesia. Inverse agonists at this subunit have nootropic effects and may be useful for the treatment of cognitive disorders such as Alzheimer's disease.
Basmisanil (RG-1662, RO5186582): derivative of Ro4938581, negative allosteric modulator at GABAA α5, in human trials for treating cognitive deficit in Down syndrome.[7]
^Wingrove P, Hadingham K, Wafford K, Kemp JA, Ragan CI, Whiting P (February 1992). "Cloning and expression of a cDNA encoding the human GABA-A receptor alpha 5 subunit". Biochem. Soc. Trans. 20 (1): 18S. doi:10.1042/bst020018s. PMID 1321750.
^McCabe, L. L.; McCabe, E. R. B. (2013). "Down syndrome and personalized medicine: Changing paradigms from genotype to phenotype to treatment". Congenital Anomalies. 53 (1): 1–2. doi:10.1111/cga.12000. PMID 23480351. S2CID 28096008.
^Savić MM, Clayton T, Furtmüller R, et al. (2008). "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats". Brain Res. 1208: 150–159. doi:10.1016/j.brainres.2008.02.020. PMC2577822. PMID 18394590.
^van Niel MB, Wilson K, Adkins CH, et al. (2005). "A new pyridazine series of GABAA alpha5 ligands". J. Med. Chem. 48 (19): 6004–6011. doi:10.1021/jm050249x. PMID 16162003.
^Ballard TM, Knoflach F, Prinssen E, et al. (2008). "RO4938581, a novel cognitive enhancer acting at GABA(A) alpha5 subunit-containing receptors". Psychopharmacology. 202 (1–3): 207–223. doi:10.1007/s00213-008-1357-7. PMID 18936916. S2CID 22011375.
^Chambers MS, Atack JR, Bromidge FA, et al. (2002). "6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists". J. Med. Chem. 45 (6): 1176–1179. doi:10.1021/jm010471b. PMID 11881985.
^Chambers MS, Atack JR, Broughton HB, et al. (2003). "Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition". J. Med. Chem. 46 (11): 2227–2240. doi:10.1021/jm020582q. PMID 12747794.
Further readingedit
Delong R (2007). "GABA(A) receptor alpha5 subunit as a candidate gene for autism and bipolar disorder: a proposed endophenotype with parent-of-origin and gain-of-function features, with or without oculocutaneous albinism". Autism. 11 (2): 135–147. doi:10.1177/1362361307075705. PMID 17353214. S2CID 44688865.
Otani K, Ujike H, Tanaka Y, et al. (2005). "The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder". Neurosci. Lett. 381 (1–2): 108–113. doi:10.1016/j.neulet.2005.02.010. PMID 15882799. S2CID 54309071.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC528928. PMID 15489334.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC139241. PMID 12477932.
Ritchie RJ, Mattei MG, Lalande M (1998). "A large polymorphic repeat in the pericentromeric region of human chromosome 15q contains three partial gene duplications". Hum. Mol. Genet. 7 (8): 1253–1260. doi:10.1093/hmg/7.8.1253. PMID 9668167.
Kim Y, Glatt H, Xie W, et al. (1997). "Human gamma-aminobutyric acid-type A receptor alpha5 subunit gene (GABRA5): characterization and structural organization of the 5' flanking region". Genomics. 42 (3): 378–387. doi:10.1006/geno.1997.4770. PMID 9205108.
Glatt K, Glatt H, Lalande M (1997). "Structure and organization of GABRB3 and GABRA5". Genomics. 41 (1): 63–69. doi:10.1006/geno.1997.4639. PMID 9126483.
Knoll JH, Sinnett D, Wagstaff J, et al. (1993). "FISH ordering of reference markers and of the gene for the alpha 5 subunit of the gamma-aminobutyric acid receptor (GABRA5) within the Angelman and Prader–Willi syndrome chromosomal regions". Hum. Mol. Genet. 2 (2): 183–189. doi:10.1093/hmg/2.2.183. PMID 8388764.
Russek SJ, Farb DH (1995). "Mapping of the beta 2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABAA receptor isoform". Genomics. 23 (3): 528–533. doi:10.1006/geno.1994.1539. PMID 7851879.
Glatt KA, Sinnett D, Lalande M (1993). "Dinucleotide repeat polymorphism at the GABAA receptor alpha 5 (GABRA5) locus at chromosome 15q11-q13". Hum. Mol. Genet. 1 (5): 348. doi:10.1093/hmg/1.5.348. PMID 1338907.
Wingrove P, Hadingham K, Wafford K, et al. (1992). "Cloning and expression of a cDNA encoding the human GABA-A receptor alpha 5 subunit". Biochem. Soc. Trans. 20 (1): 18S. doi:10.1042/bst020018s. PMID 1321750.
gabra5, gamma, aminobutyric, acid, gaba, receptor, alpha, also, known, protein, which, humans, encoded, gene, identifiersaliases, gamma, aminobutyric, acid, type, receptor, alpha5, subunit, eiee79, gamma, aminobutyric, acid, type, receptor, subunit, alpha5, de. Gamma aminobutyric acid GABA A receptor alpha 5 also known as GABRA5 is a protein which in humans is encoded by the GABRA5 gene 5 6 GABRA5IdentifiersAliasesGABRA5 gamma aminobutyric acid type A receptor alpha5 subunit EIEE79 gamma aminobutyric acid type A receptor subunit alpha5 DEE79External IDsOMIM 137142 MGI 95617 HomoloGene 20219 GeneCards GABRA5Gene location Human Chr Chromosome 15 human 1 Band15q12Start26 866 911 bp 1 End26 949 208 bp 1 Gene location Mouse Chr Chromosome 7 mouse 2 Band7 B5 7 33 52 cMStart57 057 420 bp 2 End57 159 807 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed innucleus accumbensprefrontal cortexBrodmann area 10cingulate gyrusorbitofrontal cortexdorsolateral prefrontal cortexhippocampus properRegion I of hippocampus properBrodmann area 9frontal poleTop expressed inRegion I of hippocampus properhippocampus properdentate gyrusventromedial nucleussubiculumarcuate nucleusamygdalaolfactory bulbvisual cortexsuperior colliculusMore reference expression dataBioGPSn aGene ontologyMolecular functionGABA A receptor activity transporter activity ion channel activity chloride channel activity extracellular ligand gated ion channel activity transmembrane signaling receptor activity signaling receptor activity GABA receptor binding inhibitory extracellular ligand gated ion channel activity benzodiazepine receptor activity GABA gated chloride ion channel activity transmitter gated ion channel activity involved in regulation of postsynaptic membrane potentialCellular componentintegral component of membrane cell body GABA A receptor complex postsynaptic membrane membrane receptor complex synapse integral component of plasma membrane chloride channel complex neuronal cell body membrane dendrite nucleoplasm cytosol plasma membrane cell junction GABA ergic synapse integral component of postsynaptic membrane integral component of presynaptic membrane integral component of postsynaptic specialization membrane dendrite membrane neuron projection postsynapseBiological processgamma aminobutyric acid signaling pathway negative regulation of neuron apoptotic process cochlea development associative learning regulation of neuron apoptotic process neuron development chloride transmembrane transport sensory perception of sound ion transport behavioral fear response brain development inner ear receptor cell development chloride transport innervation signal transduction chemical synaptic transmission ion transmembrane transport regulation of membrane potential nervous system process synaptic transmission GABAergic regulation of postsynaptic membrane potentialSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez2558110886EnsemblENSG00000186297ENSMUSG00000055078UniProtP31644Q8BHJ7RefSeq mRNA NM 000810NM 001165037NM 176942NM 001362161NM 001362162RefSeq protein NP 000801NP 001158509NP 795916NP 001349090NP 001349091Location UCSC Chr 15 26 87 26 95 MbChr 7 57 06 57 16 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Subunit selective ligands 2 1 Agonists 2 2 Antagonists 3 See also 4 References 5 Further reading 6 External linksFunction editGABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors which are ligand gated chloride channels Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABAA receptor At least 16 distinct subunits of GABAA receptors have been identified Transcript variants utilizing three different alternative non coding first exons have been described 5 Subunit selective ligands editRecent research has produced several ligands which are moderately selective for GABAA receptors containing the a5 subunit These have proved to be useful in investigating some of the side effects of benzodiazepine and nonbenzodiazepine drugs particularly the effects on learning and memory such as anterograde amnesia Inverse agonists at this subunit have nootropic effects and may be useful for the treatment of cognitive disorders such as Alzheimer s disease Agonists edit QH ii 066 SH 053 R CH3 2 F Antagonists edit a5IA Basmisanil RG 1662 RO5186582 derivative of Ro4938581 negative allosteric modulator at GABAA a5 in human trials for treating cognitive deficit in Down syndrome 7 L 655 708 MRK 016 PWZ 029 moderate inverse agonist 8 Pyridazines 9 Ro4938581 10 TB 21007 11 12 See also editGABAA receptorReferences edit a b c GRCh38 Ensembl release 89 ENSG00000186297 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000055078 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Entrez Gene GABRA5 gamma aminobutyric acid GABA A receptor alpha 5 Wingrove P Hadingham K Wafford K Kemp JA Ragan CI Whiting P February 1992 Cloning and expression of a cDNA encoding the human GABA A receptor alpha 5 subunit Biochem Soc Trans 20 1 18S doi 10 1042 bst020018s PMID 1321750 McCabe L L McCabe E R B 2013 Down syndrome and personalized medicine Changing paradigms from genotype to phenotype to treatment Congenital Anomalies 53 1 1 2 doi 10 1111 cga 12000 PMID 23480351 S2CID 28096008 Savic MM Clayton T Furtmuller R et al 2008 PWZ 029 a compound with moderate inverse agonist functional selectivity at GABA A receptors containing alpha5 subunits improves passive but not active avoidance learning in rats Brain Res 1208 150 159 doi 10 1016 j brainres 2008 02 020 PMC 2577822 PMID 18394590 van Niel MB Wilson K Adkins CH et al 2005 A new pyridazine series of GABAA alpha5 ligands J Med Chem 48 19 6004 6011 doi 10 1021 jm050249x PMID 16162003 Ballard TM Knoflach F Prinssen E et al 2008 RO4938581 a novel cognitive enhancer acting at GABA A alpha5 subunit containing receptors Psychopharmacology 202 1 3 207 223 doi 10 1007 s00213 008 1357 7 PMID 18936916 S2CID 22011375 Chambers MS Atack JR Bromidge FA et al 2002 6 7 Dihydro 2 benzothiophen 4 5H ones a novel class of GABA A alpha5 receptor inverse agonists J Med Chem 45 6 1176 1179 doi 10 1021 jm010471b PMID 11881985 Chambers MS Atack JR Broughton HB et al 2003 Identification of a novel selective GABA A alpha5 receptor inverse agonist which enhances cognition J Med Chem 46 11 2227 2240 doi 10 1021 jm020582q PMID 12747794 Further reading editDelong R 2007 GABA A receptor alpha5 subunit as a candidate gene for autism and bipolar disorder a proposed endophenotype with parent of origin and gain of function features with or without oculocutaneous albinism Autism 11 2 135 147 doi 10 1177 1362361307075705 PMID 17353214 S2CID 44688865 Otani K Ujike H Tanaka Y et al 2005 The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder Neurosci Lett 381 1 2 108 113 doi 10 1016 j neulet 2005 02 010 PMID 15882799 S2CID 54309071 Gerhard DS Wagner L Feingold EA et al 2004 The status quality and expansion of the NIH full length cDNA project the Mammalian Gene Collection MGC Genome Res 14 10B 2121 2127 doi 10 1101 gr 2596504 PMC 528928 PMID 15489334 Chou KC 2004 Modelling extracellular domains of GABA A receptors subtypes 1 2 3 and 5 Biochem Biophys Res Commun 316 3 636 642 doi 10 1016 j bbrc 2004 02 098 PMID 15033447 Strausberg RL Feingold EA Grouse LH et al 2003 Generation and initial analysis of more than 15 000 full length human and mouse cDNA sequences Proc Natl Acad Sci U S A 99 26 16899 16903 Bibcode 2002PNAS 9916899M doi 10 1073 pnas 242603899 PMC 139241 PMID 12477932 Ritchie RJ Mattei MG Lalande M 1998 A large polymorphic repeat in the pericentromeric region of human chromosome 15q contains three partial gene duplications Hum Mol Genet 7 8 1253 1260 doi 10 1093 hmg 7 8 1253 PMID 9668167 Kim Y Glatt H Xie W et al 1997 Human gamma aminobutyric acid type A receptor alpha5 subunit gene GABRA5 characterization and structural organization of the 5 flanking region Genomics 42 3 378 387 doi 10 1006 geno 1997 4770 PMID 9205108 Glatt K Glatt H Lalande M 1997 Structure and organization of GABRB3 and GABRA5 Genomics 41 1 63 69 doi 10 1006 geno 1997 4639 PMID 9126483 Knoll JH Sinnett D Wagstaff J et al 1993 FISH ordering of reference markers and of the gene for the alpha 5 subunit of the gamma aminobutyric acid receptor GABRA5 within the Angelman and Prader Willi syndrome chromosomal regions Hum Mol Genet 2 2 183 189 doi 10 1093 hmg 2 2 183 PMID 8388764 Russek SJ Farb DH 1995 Mapping of the beta 2 subunit gene GABRB2 to microdissected human chromosome 5q34 q35 defines a gene cluster for the most abundant GABAA receptor isoform Genomics 23 3 528 533 doi 10 1006 geno 1994 1539 PMID 7851879 Glatt KA Sinnett D Lalande M 1993 Dinucleotide repeat polymorphism at the GABAA receptor alpha 5 GABRA5 locus at chromosome 15q11 q13 Hum Mol Genet 1 5 348 doi 10 1093 hmg 1 5 348 PMID 1338907 Wingrove P Hadingham K Wafford K et al 1992 Cloning and expression of a cDNA encoding the human GABA A receptor alpha 5 subunit Biochem Soc Trans 20 1 18S doi 10 1042 bst020018s PMID 1321750 External links editGABRA5 protein human at the U S National Library of Medicine Medical Subject Headings MeSH This article incorporates text from the United States National Library of Medicine which is in the public domain nbsp This membrane protein related article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title GABRA5 amp oldid 1187955245, wikipedia, wiki, book, books, library,
