GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts atGABAA receptors, which areligand-gatedchloride channels. Chloride conductance of these channels can be modulated by agents such asbenzodiazepines 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 firstexons have been described.[5]
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 asanterograde amnesia. Inverse agonists at this subunit havenootropic effects and may be useful for the treatment of cognitive disorders such asAlzheimer's disease.
Basmisanil (RG-1662, RO5186582): derivative of Ro4938581, negative allosteric modulator at GABAA α5, in human trials for treating cognitive deficit inDown 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".Biochemical Society Transactions.20 (1): 18S.doi:10.1042/bst020018s.PMID1321750.
^McCabe LL, McCabe ER (March 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.PMID23480351.S2CID28096008.
^van Niel MB, Wilson K, Adkins CH, Atack JR, Castro JL, Clarke DE, et al. (September 2005). "A new pyridazine series of GABAA alpha5 ligands".Journal of Medicinal Chemistry.48 (19):6004–6011.doi:10.1021/jm050249x.PMID16162003.
^Ballard TM, Knoflach F, Prinssen E, Borroni E, Vivian JA, Basile J, et al. (January 2009). "RO4938581, a novel cognitive enhancer acting at GABAA alpha5 subunit-containing receptors".Psychopharmacology.202 (1–3):207–223.doi:10.1007/s00213-008-1357-7.PMID18936916.S2CID22011375.
^Chambers MS, Atack JR, Bromidge FA, Broughton HB, Cook S, Dawson GR, et al. (March 2002). "6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists".Journal of Medicinal Chemistry.45 (6):1176–1179.doi:10.1021/jm010471b.PMID11881985.
^Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, et al. (May 2003). "Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition".Journal of Medicinal Chemistry.46 (11):2227–2240.doi:10.1021/jm020582q.PMID12747794.
Delong R (March 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.PMID17353214.S2CID44688865.
Otani K, Ujike H, Tanaka Y, Morita Y, Katsu T, Nomura A, et al. (2005). "The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder".Neuroscience Letters.381 (1–2):108–113.doi:10.1016/j.neulet.2005.02.010.PMID15882799.S2CID54309071.
Kim Y, Glatt H, Xie W, Sinnett D, Lalande M (June 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.PMID9205108.
Glatt K, Glatt H, Lalande M (April 1997). "Structure and organization of GABRB3 and GABRA5".Genomics.41 (1):63–69.doi:10.1006/geno.1997.4639.PMID9126483.
Knoll JH, Sinnett D, Wagstaff J, Glatt K, Wilcox AS, Whiting PM, et al. (February 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".Human Molecular Genetics.2 (2):183–189.doi:10.1093/hmg/2.2.183.PMID8388764.
Glatt KA, Sinnett D, Lalande M (August 1992). "Dinucleotide repeat polymorphism at the GABAA receptor alpha 5 (GABRA5) locus at chromosome 15q11-q13".Human Molecular Genetics.1 (5): 348.doi:10.1093/hmg/1.5.348.PMID1338907.
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".Biochemical Society Transactions.20 (1): 18S.doi:10.1042/bst020018s.PMID1321750.
