电压门控钙通道辅助亚基α2δ-1的结构和分子药理  

The Structure and Molecular Pharmacology of Voltage-gated Calcium Channel Auxiliary Subunits α2δ-1

作　　者：瞿芳 陈可之 陈金军 QU Fang;CHEN Ke-Zhi;CHEN Jin-Jun(Department of Biotechnology,College of Bioscience and Biotechnology,Hunan Agricultural University,Changsha 410128,China)

机构地区：[1]湖南农业大学生物科学技术学院生物技术系,长沙410128

出　　处：《中国生物化学与分子生物学报》2020年第8期872-878,共7页Chinese Journal of Biochemistry and Molecular Biology

基　　金：湖南省教育厅基金会赠款(No.16A098);湖南省科技厅重点科研项目(No.2017NK2311)资助。

摘　　要：电压门控钙通道(voltage-gated calcium channel, VGCC)辅助亚基α2δ-1在神经元兴奋传递中起促进作用,是加巴喷丁(gabapentin)和普瑞巴林(pregabalin)的作用靶点。α2δ-1由高度糖基化的α2亚基和δ亚基以4对二硫键相连,包含4个串联的Cache结构域和1个von Willebrand A结构域,但δ亚基的C-末端结构尚未完全解析。α2δ-1的结构和作用机制研究进展主要聚焦于以下3点:(1)α2δ-1的C-末端,传统观点认为含有跨膜基序(motif)。另一个观点认为是GPI锚定,尚缺乏直接的实验证明;(2)α2δ-1对电压门控钙离子通道的影响,包括直接的和非直接的调控对电压门控钙通道的膜上转运和电流的影响,以及α2δ-1的翻译后修饰对钙电流的影响;(3)α2δ-1不依赖于钙通道,而与其他蛋白质存在相互作用,互作效应表现在兴奋性电流增大或促进神经突触发生。在疾病研究方面,本文主要综述α2δ-1在慢性疼痛中的机制研究。α2δ-1参与的生理活动的分子机制复杂,现已突破传统的局限于电压门控钙通道辅助亚基的角色,并将有可能通过α2δ-1建立跨细胞膜的蛋白质-蛋白质相互作用网络的动态膜微区,以进一步评估其生理、病理和药理的相关性。Voltage-gated calcium channel(VGCC) auxiliary subunits α2δ-1 plays a promoter in neuronal excitatory transmission and is the target of gabapentin and pregabalin. α2δ-1 is composed of highly glycosylated α2 and δ subunits connected by four pairs of disulfide bonds, including four Cache domains and a von Willebrand A domain, but the C-terminal structure of the δ subunit is not yet clear and controversial. The studies of the structure and mechanism of α2δ-1 mainly focus on the following three points:(1) The C-terminal of α2δ-1 is traditionally believed to contain a transmembrane motif, while it is believed to be GPI anchored, which is yet to be proved by direct experiments. However, the study of protein-protein interaction suggests that it is a transmembrane protein;(2) The effects of α2δ-1 on VGCC include the effects of direct and indirect regulation on VGCC membrane forward trafficking and current, as well as post-translational modification of α2δ-1 on calcium-current levels.(3) α2δ-1 does not depend on VGCC, but interacts with other proteins. The interactions can increase excitatory current or promote synaptogenesis. In terms of disease research, this paper mainly reviews the mechanism of α2δ-1 in chronic pain. Due to the complex molecular mechanisms involved in the physiological activities of α2δ-1, the traditional role as an auxiliary subunit of voltage-gated calcium channel has been broken through, and it will be possible to establish the dynamic membrane micro-region of the protein-protein interaction network across the cell membrane through α2δ-1, so as to further evaluate its physiological, pathological and pharmacological correlations.

关 键 词：α2δ-1 电压门控钙通道 NMDA受体 蛋白质-蛋白质相互作用 神经痛 加巴喷丁 

分 类 号：Q71[生物学—分子生物学]