Alternative titles; symbols
HGNC Approved Gene Symbol: GABRA6
Cytogenetic location: 5q34 Genomic coordinates (GRCh38): 5:161,685,721-161,702,592 (from NCBI)
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRA6 is a member of the GABA-A receptor gene family of heteromeric pentameric ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the mammalian brain, acts. GABA-A receptors are the site of action of a number of important pharmacologic agents including barbiturates, benzodiazepines, and ethanol (summary by Whiting et al., 1999).
For additional general information about the GABA-A receptor gene family, see GABRA1 (137160).
Korpi et al. (1993) presented evidence that cerebellar motor control may be a distinct behavioral correlate of the alpha-6-subunit-containing GABA-A receptor subtype. The selectively outbred alcohol-nontolerant (ANT) rat line is highly susceptible to impairment of postural reflexes by benzodiazepine agonists such as diazepam. ANT cerebella are generally devoid of diazepam-insensitive high-affinity binding of a benzodiazepine, whereas in nonselected strains such binding marks a granule-cell-specific GABA-A receptor containing the alpha-6 subunit. A critical determinant for diazepam insensitivity of this 'wildtype' cerebellar GABA-A receptor is an arginine residue at position 100 of alpha-6 where other alpha subunits carry a histidine. Korpi et al. (1993) reported that the alpha-6 gene of ANT rats is expressed at wildtype levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. In consequence, the mutant receptors show diazepam-mediated potentiation of GABA-activated currents and diazepam-sensitive binding of benzodiazepine.
Hicks et al. (1994) presented further evidence for clustering of the GABRA subunit genes by mapping GABRA6 to distal chromosome 5q using a microsatellite polymorphism within the gene to study a human/hamster hybrid cell-line panel and to perform linkage analysis in the CEPH reference families. They showed that the GABRA1 (137160) and GABRA6 genes are tightly linked; maximum lod score = 39.87 at theta = 0.069 for males and 0.100 for females. GABRG2 (137164) maps to the same area, 5q31.1-q33.1; GABRA1 maps to 5q34-q35. Hicks et al. (1994) cited pulsed-field restriction mapping revealing that the maximum distance separating GABRA1 and GABRG2 is 200 kb; it could not be ruled out that these 2 genes lie adjacent to one another.
Radel et al. (2005) genotyped a Southwestern Native American sample of 433 individuals and a Finnish sample of 511 individuals, including both alcohol-dependent (103780) and unaffected individuals, for 6 SNPs in the GABA-A receptor gene cluster on chromosome 5q34. Sib-pair linkage and case-control association analyses as well as linkage disequilibrium mapping with haplotypes were done. Radel et al. (2005) detected sib-pair linkage of 5q34 GABA-A receptor genes to alcohol dependence in both population samples. Haplotype localization implicated 3 polymorphisms of GABRA6, including a pro385-to-ser substitution.
Jones et al. (1997) created mice deficient in the alpha-6 subunit of the GABA-A receptor by targeted disruption. In alpha-6 -/- granule cells, the delta subunit (GABRD; 137163) was selectively degraded, as demonstrated by immunoprecipitation, immunocytochemistry, and immunoblot analysis for delta subunit-specific antibodies. The delta subunit mRNA was present at wildtype levels in the mutant granule cells, indicating a posttranslational loss of the delta subunit. Jones et al. (1997) concluded that their results provide genetic evidence for a specific association between the alpha-6 and delta subunits. Despite deficiency of alpha-6 and delta subunits, these mice showed no behavioral abnormalities.
Many neurons receive a continuous, or 'tonic,' synaptic input, which increases their membrane conductance and so modifies the spatial and temporal integration of excitatory signals. In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA gives rise to a persistent conductance mediated by the GABA-A receptor that also modifies the excitability of granule cells. Brickley et al. (2001) showed that this tonic conductance was absent in granule cells from mice lacking the alpha-6 and delta subunits of the GABA-A receptor. The response of these granule cells to excitatory synaptic input remained unaltered, owing to an increase in a 'leak' conductance, which was present at rest, with properties characteristic of the 2-pore-domain potassium channel TASK1 (603220). Brickley et al. (2001) concluded that their results highlight the importance of tonic inhibition mediated by GABA-A receptors, loss of which triggers a form of homeostatic plasticity leading to a change in the magnitude of a voltage-independent potassium conductance that maintains normal neuronal behavior.
Brickley, S. G., Revilla, V., Cull-Candy, S. G., Wisden, W., Farrant, M. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409: 88-92, 2001. [PubMed: 11343119] [Full Text: https://doi.org/10.1038/35051086]
Hicks, A. A., Bailey, M. E. S., Riley, B. P., Kamphuis, W., Siciliano, M. J., Johnson, K. J., Darlison, M. G. Further evidence for clustering of human GABA-A receptor subunit genes: localization of the alpha-6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis. Genomics 20: 285-288, 1994. [PubMed: 8020978] [Full Text: https://doi.org/10.1006/geno.1994.1167]
Jones, A., Korpi, E. R., McKernan, R. M., Pelz, R., Nusser, Z., Makela, R., Mellor, J. R., Pollard, S., Bahn, S., Stephenson, F. A., Randall, A. D., Sieghart, W., Somogyi, P., Smith, A. J., Wisden, W. Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci. 17: 1350-1362, 1997. [PubMed: 9006978] [Full Text: https://doi.org/10.1523/JNEUROSCI.17-04-01350.1997]
Korpi, E. R., Kleingoor, C., Kettenmann, H., Seeburg, P. H. Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABA-A receptor. Nature 361: 356-359, 1993. [PubMed: 7678923] [Full Text: https://doi.org/10.1038/361356a0]
Radel, M., Vallejo, R. L., Iwata, N., Aragon, R., Long, J. C., Virkkunen, M., Goldman, D. Haplotype-based localization of an alcohol dependence gene to the 5q34 gamma-aminobutyric acid type A gene cluster. Arch. Gen. Psychiat. 62: 47-55, 2005. [PubMed: 15630072] [Full Text: https://doi.org/10.1001/archpsyc.62.1.47]
Whiting, P. J., Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J. S., Thompson, S. A., Wafford, K. A. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann. N.Y. Acad. Sci. 868: 645-653, 1999. [PubMed: 10414349] [Full Text: https://doi.org/10.1111/j.1749-6632.1999.tb11341.x]