GABRA6

Gamma-aminobutyric acid receptor subunit α-6 (GABRA6), also known as GABA-A receptor subunit α6, is a protein encoded by the GABRA6 gene in humans. It has always been considered an important target for the etiology and treatment of epilepsy.

Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in GABAergic neurotransmission in the mammalian central nervous system. GABRA6 is a member of the GABA-a receptor gene family of heteromeric pentameric ligand-gated ion channels. GABA, the main inhibitory neurotransmitter in the mammalian brain, acts through GABRA. The GABA-A receptor is the site of action for many important drugs, including barbiturates, benzodiazepines and ethanol. These also have certain applicability to GABRA6.

GABRA6 Gene Mapping

Hicks et al. used intragenic microsatellite polymorphism to map GABRA6 to human distal chromosome 5q. Further through linkage analysis of human/hamster hybrid cell lines, they found that GABRA1 and GABRA6 genes are closely linked.

GABRA6 Function

Figure 1. Shown is a common subtype α1β2γ2 of GABAA receptors found in the mammalian CNS.(Gong P, et al.; 2015)

GABA is the main inhibitory neurotransmitter in the mammalian brain. About 30% of the central nerve synapses use GABA as the transmitter. Studies have shown that GABA-A receptors play a central role in controlling neuronal maturation and hippocampal neurogenesis, as well as reducing the excitability of neurons in the entire central nervous system. Recently, it has been reported that there is an association between interfering gamma-aminobutyric acid (GABA)-mediated inhibition and neuropsychiatric diseases. As a member of the GABA receptor family, GABRA6 is preferentially expressed in cerebellar granule neurons. Moreover, clinical studies have shown that differences in GABRA6 are related to pathological risks, including anxiety, drug and alcohol dependence, and schizophrenia.

GABRA6 Clinical Study

Korpi et al. proposed in 1993 that cerebellar motor control may be related to the unique behavior of GABA-A receptor subtypes containing α-6 subunits. The GABAA receptor is the gated receptor of the chloride ion channel, and the Cl-channel is composed of two α and two β subunits (α2β2). There are GABA receptors on the β subunit. When GABA binds to it, the Cl- channel opens and Cl- inflows, which makes the nerve cells hyperpolarize and produces an inhibitory effect. There are benzodiazepine receptors on the α subunit. When benzodiazepine binds to it, it cannot open the Cl-channel, but it promotes the binding of GABA and GABAA receptors to open the Cl-channel frequency Increase (not to extend the Cl- channel opening time or increase the Cl- flow), more Cl- internal flow. Therefore, benzodiazepines can enhance GABAergic neurotransmission and synaptic inhibition, as well as enhance the combination of GABA and GABAA receptors. Therefore, benzodiazepine is commonly used clinically for anti-anxiety, sedation and hypnosis.

GABRA6 and Disease

The glucocorticoid component of stress response has become the focus of scientific research, because excessive glucocorticoid exposure can lead to a wide range of pathological consequences, including mood and anxiety disorders and cognitive impairment. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenal medulla system. These nervous systems are regulated by neuronal pathways, including the inhibitory GABA system. About 60% of the differences in glucocorticoid levels may be due to genetic individual differences. A previous study found that the T1521C variant in the GABRA6 gene is related to specific personality characteristics and a significant reduction in the response of hormones and blood pressure to psychological stress.

In addition, through genetic analysis and comparative analysis, the researchers found that GABRA6 also showed a developmental correlation with alcoholism similar to the GABRA1 receptor.

References

1. Uhart M, et al.; GABRA6 gene polymorphism and an attenuated stress response. Mol Psychiatry. 2004, 9(11):998-1006.
2. Hicks, A. A., et al.; 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. 1994, 20: 285-288.
3. Korpi, E. R., et al.; Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABA-A receptor. Nature. 1993, 361: 356-359.
4. Radel, M., et al.; Haplotype-based localization of an alcohol dependence gene to the 5q34 gamma-aminobutyric acid type A gene cluster. Arch. Gen. Psychiat. 2005, 62: 47-55.
5. Gong P, et al.; Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers. Biomarkers in Medicine. 2015, 9(11), 1225-39.