Elsevier

Gene

Volume 809, 30 January 2022, 146021
Gene

GABRB2, a key player in neuropsychiatric disorders and beyond

https://doi.org/10.1016/j.gene.2021.146021Get rights and content

Highlights

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    GABRB2 encodes the β2 subunit of GABAA receptors which is essential for fast-acting inhibitory neurotransmission through ligand-gated chloride channels.

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    GABRB2 is highly and broadly expressed in the brain under physiological conditions, and may also be expressed at tumorous sites outside of the central nervous system such as thyroid cancer.

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    GABRB2 expression is subject to specific epigenetic regulations in form of partial maternal genomic imprinting.

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    GABRB2 is involved in the pathophysiology of a range of neuropsychiatric disorders such as schizophrenia.

Abstract

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. GABAA 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 GABAA receptors, which account for 43% of all GABAA 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.

Introduction

The equilibrium between excitatory and inhibitory systems leads to the normal functioning of the brain (Sigel and Ernst, 2018). The γ-aminobutyric acid (GABA) system is the major inhibitory system in the mammalian central nervous system (CNS). Enhancement of GABA transmission in the hippocampus protects its structure and function, and increased excitability and decreased inhibitory functions mediated by the GABA system are associated with memory impairment (Ylinen et al., 1991). The GABA system is also involved in the modulation of the stress response by inhibiting the hypothalamic–pituitaryadrenal (HPA) axis (Herman et al., 2004).

There are three types of GABA receptors: the metabotropic GABAB receptors and the inotropic GABAA and GABAC receptors (Li et al., 2006). GABAA receptors are ligand-gated chloride channels that belong to the Cys-loop superfamily. This family also includes the nicotinic acetylcholine receptor (nAChR), the 5-hydroxytryptamine type-3 (5-HT3) receptor, and the glycine receptor. GABAA receptors mediate a fast inhibition via the opening of chloride ion pore formed by the assembly of different GABAA receptor subunits (Saxena and Macdonald, 1994, Sparling and DiMauro, 2017). The major isoform of the GABAA receptor in the brain is composed of two α1, two β2, and one γ2 subunits that are encoded by the GABRA1, GABRB2, and GABRG2 genes, respectively, which are located on the 5q GABAA receptor subunit gene cluster. GABRB2 has been associated with schizophrenia, bipolar disorder, epilepsy, autism spectrum disorder, Alzheimer’s disease, frontotemporal dementia, depression, internet gaming disorder, premenstrual dysphoric disorder, and cancer. It also contributes to the genetic susceptibility to substance dependence (Hirose, 2014, Kim et al., 2015).

The present review provides information from published reports and public databases including PubMed and Google Scholar on GABAA receptors, and on the structure, regulation, function, and role in human diseases of the GABRB2 gene.

Section snippets

GABAA receptors

GABAA receptor is heteropentameric in structure (Fig. 1A), and contains five of the following subunits belonging to different families: α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1–3) (Sparling and DiMauro, 2017). Subunits in the same family share 60 to 80% of sequence identity while subunits from different families are 20 to 40% common in sequence (Saxena and Macdonald, 1994). Most subunit genes are grouped to form clusters on chromosomes 4, 5, 15, and X. The molecular composition of the

Structure, expression, and regulation of GABRB2

The GABRB2 gene is located on chromosome 5 at 5q34, spanning>260 kb and composed of 11 exons (Table 2). The open reading frame spans from exon 2 to exon 11 and encodes the GABAA receptor β2 subunit (Fig. 2A). The promoter region is located from 1000 bp upstream to 689 bp downstream in exon 1. GABRB2 is highly expressed in the brain with abundance in the gray matter of neurons and glial cells (Russek and Farb, 1994, Zhao et al., 2006). It is concentrated in different parts of the brain including

Functions of GABRB2

In the immature brain, GABAA receptors play a crucial role in neurogenesis and synaptogenesis. The GABA system stimulates neuronal growth in the hippocampus (Ben-Ari et al., 2007). GABA transmission is also implicated in cortical development, exercising a paracrine action and stimulating the release of brain-derived neurotrophic factor (BDNF) by postsynaptic neurons that would enhance GABA transmission (Obrietan et al., 2002). As well, the GABA system contributes to the activation of

Role of GABRB2 in human diseases

Polygenic diseases are disorders caused by the interaction between multiple genetic and environmental factors whereas monogenic diseases are caused by mutations in a single gene. while single nucleotide polymorphisms in genome-wide association studies and altered copy number variations are often identified as risk factors, single-gene mutations are regarded more as causal factors (May et al., 2018).

GABRB2 plays an important role in the formation of the pentameric structure of the GABAA

Therapeutic implications of β2 subunit

It was reported that GABAA receptors showed a higher sensitivity to GABA when the receptor contains more β2 than α subunits (Hartiadi et al., 2016). Mutations at tyrosine residues of the β2 subunit significantly reduced GABA binding rates (Laha and Tran, 2013); and proline residues in the Cys-loop were important for a rapid response to GABAA receptor agonists (Tierney et al., 2008). The β2 subunit also contributed to the binding of alcohol and anesthetics including etomidate and propofol (

Conclusion

The GABAA receptors play crucial roles in the central nervous system on account of being the major emitters of negative signaling in the human brain. Accordingly, in addition to the importance of these receptors and their genes to the operation of the human brain and the pathophysiology of diseases, a deeper understanding of their structures and functions will be essential to future advances in learning and memory, the delineation of their actions in a variety of neurodegenerative and other

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This review is part of the Gene Wiki Review series, a collaboration between the journal GENE and the Gene Wiki Initiative supported by National Institutes of Health (GM089820) and by Elsevier.

The corresponding Gene Wiki entry for this review can be found here: https://en.wikipedia.org/wiki/GABRB2.

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