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蛋白质水解对电压门控Ca2+通道的调节

Abele Kathryn, 杨 建

哥伦比亚大学生物学系，纽约，纽约州 10027，美国

摘要

电压门控Ca2+通道是由多个亚基组成的膜蛋白，其分布广泛，生理功能极为重要，可被众多蛋白和信号传导通路调节。本综述重点介绍蛋白质水解对电压门控Ca2+通道的调节作用及其生理功能。Ca2+通道的主亚基Cavα1可被蛋白质水解，从而调控Ca2+通道的功能和降解，影响基因表达和细胞兴奋性。根据其组织分布，L类Ca2+通道有两种水解模式：在心脏和骨骼肌，Cavα1的羧基末端被水解后与剩余的羧基端结合，抑制Ca2+通道电流。这种自身抑制可被体内分泌的肾上腺素解除，引发心肌和骨骼肌Ca2+电流大量增加，在“打或逃”之类的应激反应中起重要作用，Cavα1羧基末端水解在大脑也存在，并可能是由calpain蛋白质水解酶催化；在某些大脑区域，Cavα1的整个羧基端可被水解并迁移至细胞核，起到转录因子的作用。P/Q类Ca2+通道Cavα1的羧基末端也可被水解，并迁移到细胞核。许多基因突变产生截断型P/Q Cavα1，而这些截断型Cavα1可严重影响正常Ca2+通道的功能，导致人类的疾病。截断型N类Ca2+通道Cavα1可通过诱变产生，影响正常通道的表达。新型Ca2+通道水解新模式可能是未来Ca2+通道研究中一个重要的探索方向。

关键词： 离子通道; 钙信号; 蛋白酶解加工; 调节; 离子通道疾病; 基因表达

分类号：R337.5；R338.2

Regulation of voltage-gated calcium channels by proteolysis

Abele Kathryn, Yang Jian

Department of Biological Sciences, Columbia University, New York, NY 10027, USA

Abstract

Voltage gated calcium channels (VGCCs) are multi-subunit membrane proteins present in a variety of tissues and control many essential physiological processes. Due to their vital importance, VGCCs are regulated by a myriad of proteins and signaling pathways. Here we review the literature on the regulation of VGCCs by proteolysis of the pore-forming α1 subunit, Ca(v)α(1). This form of regulation modulates channel function and degradation and affects cellular gene expression and excitability. L-type Ca(2+) channels are proteolyzed in two ways, depending on tissue localization. In the heart and skeletal muscle, the distal C-terminus of Ca(v)α(1) is cleaved and acts as an autoinhibitor when it reassociates with the proximal C-terminus. Relief of this autoinhibition underlies the β-adrenergic stimulation-induced enhancement of cardiac and skeletal muscle calcium currents, part of the "fight or flight" response. Proteolysis of the distal C-terminus of L-type channels also occurs in the brain and is probably catalyzed by a calpain-like protease. In some brain regions, the entire C-terminus of L-type Ca(2+) channels can be cleaved by an unknown protease and translocates to the nucleus acting as a transcription factor. The distal C-terminus of P/Q-channel Ca(v)α(1) is also proteolyzed and translocates to the nucleus. Truncated forms of the PQ-channel Ca(v)α(1) are produced by many disease-causing mutations and interfere with the function of full-length channels. Truncated forms of N-type channel Ca(v)α(1), generated by mutagenesis, affect the expression of full-length channels. New forms of proteolysis of VGCC subunits remain to be discovered and may represent a fruitful area of VGCC research.

Key words: ion channels; calcium signaling; proteolytic processing; modulation; channelopathy; gene expression

收稿日期：2012-09-28　　录用日期：2012-10-09

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引用本文：

Abele Kathryn, 杨 建. 蛋白质水解对电压门控Ca2+通道的调节[J]. 生理学报 2012; 64 (5): 504-514.

Abele Kathryn, Yang Jian. Regulation of voltage-gated calcium channels by proteolysis. Acta Physiol Sin 2012; 64 (5): 504-514 (in Chinese with English abstract).