蛋白质水解对电压门控Ca^(2+)通道的调节(英文)  

Regulation of voltage-gated calcium channels by proteolysis

作　　者：杨建[1] ABELE Kathryn 

机构地区：[1]哥伦比亚大学生物学系,美国纽约,纽约州10027

出　　处：《生理学报》2012年第5期504-514,共11页Acta Physiologica Sinica

基　　金：supported by National Institutes of Health,USA grant RO1 NS053494;the Top Talents Program of Yunnan Province,China(J.Y.)

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/QCavα1,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。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 α 1 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.

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[医药卫生—人体生理学] R338.2[医药卫生—基础医学]