Voltage- and calcium-dependent inactivation in high voltage-gated Ca²⁺ channels

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• 作者：T. Cens ; M. Rousset ; J.-P. Leyris ; P. Fesquet and P. Charnet
• 关键词：Voltage-gated calcium channels ; Ca-dependent inactivation ; Voltage-dependent inactivation ; Calmodulin ; Auxiliary subunits
• 刊名：Progress in Biophysics and Molecular Biology
• 出版年：2006
• 期刊代码：131_00796107
• 类别：bio
• 出版时间：January-April 2006
• 卷：90
• 期：1-3
• 页码：104-117
• 文件大小：508 K

摘要

Calcium influx into cardiac myocytes via voltage-gated Ca channels is a key step in initiating the contractile response. During prolonged depolarizations, toxic Ca²⁺ overload is prevented by channel inactivation occurring through two different processes identified by their primary trigger: voltage or intracellular Ca²⁺. In physiological situations, cardiac L-type (Ca_V1.2) Ca²⁺ channels inactivate primarily via Ca²⁺-dependent inactivation (CDI), while neuronal P/Q (Ca_V2.1) Ca²⁺ channels use preferentially voltage-dependent inactivation (VDI). In certain situations however, these two types of channels have been shown to be able to inactivate by both processes.

From a structural view point, the rearrangement occurring during CDI and VDI is not precisely known, but functional studies have underlined the role played by at least 2 channel sequences: a C-terminal binding site for the Ca²⁺ sensor calmodulin, essential for CDI, and the loop connecting domains I and II, essential for VDI. The conserved regulation of VDI and CDI by the auxiliary channel β subunit strongly suggests that these two mechanisms may use a set of common protein–protein interactions that are influenced by the auxiliary subunit. We will review our current knowledge of these interactions. New data are presented on L-P/Q (Ca_V1.2/Ca_V2.1) channel chimera that confirm the role of the I–II loop in VDI and CDI, and reveal some of the essential steps in Ca²⁺ channel inactivation.