GABRA4

As we all know, γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain. Its main function is to bind to the ligand-gated chloride channel GABA-A receptor, thereby controlling the intracellular levels of chloride ions and other anions. At least 16 different GABA-A receptor subunits have been identified. Studies have found that GABRA4 (γ-aminobutyric acid type A receptor subunit Alpha4) is present on human chromosome 4p12. This gene encodes the subunit α4 of GABA-A receptors, and finally passes through another subunit, namely γ -GABA receptor β-1 (GABRB1), interact with each other to increase the risk of autism.

Figure 1. Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4. (Quadrato G, et al.; 2014)

GABAAR is a hetero-oligomeric complex composed of five transmembrane subunits, which are differentially expressed in various regions of the brain and spinal cord. Many cDNAs of GABAAR subunits and subtypes (α1-6, β1-4, γ1-3, δ, ε, π, τ and ρ1-3) have been isolated. Subunits are expressed differently by differences in the region of existence and developmental specificity. It is particularly important to understand the factors that control the levels of GABAAR subunits, because different subunits assemble into specific subtypes in different regions and have differences in the characteristic response to GABA and the response to GABA allosteric modulators. In addition, the results of some studies suggest that changes in GABAAR function are the basis of the disease phenotype.

GABRA4 Related Diseases

Autism

Autism is a common neurodevelopmental disease with important genetic components. Existing studies have shown that multiple genes cause autism, and epigenetic effects or gene-gene interactions may be the triggers for the risk of autism. However, these effects have not yet been determined.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult brain and is related to the cause of autism. Fourteen known autosomal GABA receptor subunit genes were studied to find genes related to autism and their possible interactions. Through SNPs analysis of GABRG1, GABRA2, GABRA4 and GABRB1 on chromosome 4p12 and GABRB2, GABRA6, GABRA1, GABRG2 and GABRP on chromosome 5q34-q35.1, GABRA4 was finally found to be involved The etiology of autism and the risk of autism may be increased by interacting with GABRB1.

Premenstrual Syndrome

In the brains of men and women, the hormone progesterone is easily converted to 3a-OH-5a pregnan-20-one (3a, 5a-THP). Further research found that 3a, 5a-THP acts like a sedative in the brain. It reduces anxiety and reduces seizure activity by enhancing the function of the brain's main inhibitory neurotransmitter GABA (γ-aminobutyric acid). The symptoms of premenstrual syndrome (PMS), such as anxiety and susceptibility to seizures, are related to a sharp drop in circulating levels of progesterone and a sharp drop in the levels of 3a, 5a-THP in the brain. Sudden cessation of sedatives such as benzodiazepines and ethanol can also produce withdrawal symptoms similar to PMS. In rat models of PMS and postpartum syndrome, the withdrawal of progesterone affects gene transcription, resulting in increased epilepsy sensitivity and insensitivity to benzodiazepine sedatives. Specifically, this effect is attributed to the reduced 3a,5a-THP level, which enhances the transcription of the gene encoding the a4 subunit of the GABAA receptor. In addition, the increased susceptibility to seizures after discontinuation of progesterone is due to the six-fold reduction in the decay time of the GABA current, thereby inhibiting function. Blocking the a4 gene transcript can prevent these withdrawal properties. Therefore, the symptoms of PMS may be partly attributable to changes in the expression of GABAA receptor subunits caused by progesterone withdrawal.

References

1. Collins AL, et al.; Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics. 2006, 7(3):167-74.
2. Smith SS, et al.; GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature. 1998, 392(6679):926-30.
3. Ma DQ, et al.; Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet. 2005, 77(3):377-88.
4. Roberts DS, et al.; Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. Proc Natl Acad Sci USA. 2005, 102(33):11894-9.
5. Quadrato G, et al.; Modulation of GABAA receptor signaling increases neurogenesis and suppresses anxiety through NFATc4. J Neurosci. 2014, 34(25):8630-45.