Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation.
Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation.
复制标题
DOI：
10.1085/jgp.200810143
复制
发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Minor DL Jr
中科院分区：
文献类型：
--
作者：
Findeisen F;Minor DL Jr
电压门控钙通道（CaV）失活主要有两个过程：电压依赖性失活（VEP）和钙依赖性失活（CDI）。CaVβ/CaVα1-I-II环和Ca 2 +/钙调蛋白（CaM）/CaVα1-C-末端尾复合物已被证明分别调节各自。然而，每种复合物如何与孔偶联以及每种复合物是否独立地影响失活仍然没有解决。在这里，我们证明了IS 6-α-相互作用结构域（AID）接头在孔和CaVβ/I-II环复合物之间提供了刚性连接，表明IS 6-AID接头聚甘氨酸突变加速了CaV1.2（L型）和CaV2.1（P/Q型）的降解。值得注意的是，破坏刚性IS 6-AID接头连接或破坏CaVβ/I-II结合的突变会急剧减慢CDI并减少第二个Ca 2 +/CaM/CaVα1-C末端介导的过程，称为钙依赖性易化。总的来说，数据强烈表明，传统上仅与CaVβ和IS 6-AID接头相关的组分对于钙依赖性调节是必需的，并且CaVβ依赖性和CaM依赖性组分通过需要CaVβ和完整的IS 6-AID接头的共同机制与孔偶联。
Two processes dominate voltage-gated calcium channel (CaV) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The CaVβ/CaVα1-I-II loop and Ca2+/calmodulin (CaM)/CaVα1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–α-interaction domain (AID) linker provides a rigid connection between the pore and CaVβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate CaV1.2 (L-type) and CaV2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt CaVβ/I-II association sharply decelerate CDI and reduce a second Ca2+/CaM/CaVα1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, CaVβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both CaVβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring CaVβ and an intact IS6-AID linker.
登录
查看更多内容
影响因子：
3.8
作者：
Babich, Olga;Matveev, Victor;Harris, Andrew L;Shirokov, Roman
通讯作者：
Shirokov, Roman
影响因子：
5.7
作者：
Fallon, JL;Halling, DB;Quiocho, FA
通讯作者：
Quiocho, FA
影响因子：
2.9
作者：
EDELHOCH, H
通讯作者：
EDELHOCH, H
影响因子：
64.8
作者：
Dick, Ivy E.;Tadross, Michael R.;Yue, David T.
通讯作者：
Yue, David T.
影响因子：
5.5
作者：
Findlay, I
通讯作者：
Findlay, I