GABRB2, a key player in neuropsychiatric disorders and beyond
GABRB2, a key player in neuropsychiatric disorders and beyond
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DOI：
10.1016/j.gene.2021.146021
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发表时间：
2021-10-28
期刊：
影响因子：
3.5
通讯作者：
Xue, Hong
中科院分区：
文献类型：
--
作者：
Barki, Manel;Xue, Hong
GABA 受体代表中枢神经系统中的主要抑制系统，确保突触发生、神经发生以及神经元可塑性和学习的调节。 GABAA 受体为五聚体结构，属于Cys 环超家族。 GABRB2基因位于染色体5q34上，编码β(2)亚基，与α和γ亚基结合形成GABAA受体的主要亚型，占哺乳动物大脑中所有GABAA受体的43%。每个亚基可能由一个胞外 N 端结构域、四个跨膜片段、TM3 和 TM4 之间的一个大胞内环以及一个胞外 C 端结构域组成。 GABRB2 基因的 RNA 转录物的选择性剪接至少产生四种具有不同电生理特性的长亚型和短亚型。此外，GABRB2 被印记并受到表观遗传调控和正选择。它首先在汉族人中与精神分裂症相关，随后在其他人群中得到验证。 Gabrb2 基因敲除小鼠还表现出类似精神分裂症的行为和神经炎症，抗精神病药物利培酮可以改善这些行为。 GABRB2还与其他神经精神疾病相关，包括双向情感障碍、癫痫、自闭症谱系障碍、阿尔茨海默病、额颞叶痴呆、物质依赖、抑郁症、网络游戏障碍和经前焦虑症。最近，有人推测 GABRB2 可能是不同癌症类型的潜在标志物。由于GABRB2在中枢神经系统中发挥着关键作用，并且人们越来越认识到它与人类疾病有关，因此对其结构和功能的进一步了解可能会加速新治疗方法的产生。
The GABA receptors represent the main inhibitory system in the central nervous system that ensure synapto-genesis, 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 beta(2) subunit that combines with the alpha and gamma 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 schizo-phrenia 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, ep-ilepsy, 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.