GABRB2, a key player in neuropsychiatric disorders and beyond

The GABA receptors represent the main inhibitory system in the central nervous system that ensure synaptogenesis, neurogenesis, and the regulation of neuronal plasticity and learning. GABA_A receptors are pentameric in structure and belong to the Cys-loop superfamily. The GABRB2 gene, located on chromosome 5q34, encodes the β₂ subunit that combines with the α and γ subunits to form the major subtype of GABA_A receptors, which account for 43% of all GABA_A receptors in the mammalian brain. Each subunit probably consists of an extracellular N-terminal domain, four membrane-spanning segments, a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain. Alternative splicing of the RNA transcript of the GABRB2 gene gives rise at least to four long and short isoforms with dissimilar electrophysiological properties. Furthermore, GABRB2 is imprinted and subjected to epigenetic regulation and positive selection. It has been associated with schizophrenia first in Han Chinese, and subsequently validated in other populations. Gabrb2 knockout mice also exhibited schizophrenia-like behavior and neuroinflammation that were ameliorated by the antipsychotic drug risperidone. GABRB2 was also associated with other neuropsychiatric disorders including bipolar disorder, epilepsy, autism spectrum disorder, Alzheimer's disease, frontotemporal dementia, substance dependence, depression, internet gaming disorder, and premenstrual dysphoric disorder. Recently, it has been postulated that GABRB2 might be a potential marker for different cancer types. As GABRB2 has a pivotal role in the central nervous system and is increasingly recognized to contribute to human diseases, further understanding of its structure and function may expedite the generation of new therapeutic approaches.