Calcium-dependent regulation of the voltage-gated sodium channel hH1: Intrinsic and extrinsic sensors use a common molecular switch
Calcium-dependent regulation of the voltage-gated sodium channel hH1: Intrinsic and extrinsic sensors use a common molecular switch
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DOI：
10.1073/pnas.0507397103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Chazin, WJ
中科院分区：
文献类型：
--
作者：
Shah, VN;Wingo, TL;Chazin, WJ
人心脏电压门控钠通道Nav1.5（hH 1）的功能部分地通过钙与C-末端胞质结构域中的EF手的结合来调节。hH 1也通过钙调蛋白（CaM）介导的外源性钙敏感途径调节，通过结合到紧邻EF-手结构域的IQ基序。内在EF-手结构域显示与IQ基序相互作用，IQ基序控制钙亲和力。值得注意的是，IQ残基的突变对CaM亲和力只有很小的影响，但大大降低了EF-手结构域的钙亲和力，而Brugada突变A1924 T显著降低了CaM亲和力，但对EF-手结构域的钙亲和力没有影响。此外，突变的生化效应的差异直接与通道电生理学的对比效应相关。提出了一个全面的模型，其中的hH 1 IQ基序作为一个分子开关，耦合的内在和外在的钙传感器。
The function of the human cardiac voltage-gated sodium channel Nav1.5 (hH1) is regulated in part by binding of calcium to an EF hand in the C-terminal cytoplasmic domain. hH1 is also regulated via an extrinsic calcium-sensing pathway mediated by calmodulin (CaM) via binding to an IQ motif immediately adjacent to the EF-hand domain. The intrinsic EF-hand domain is shown here to interact with the IQ motif, which controls calcium affinity. Remarkably, mutation of the IQ residues has only a minor effect on CaM affinity but drastically reduces calcium affinity of the EF-hand domain, whereas the Brugada mutation A1924T significantly reduces CaM affinity but has no effect on calcium affinity of the EF-hand domain. Moreover, the differences in the biochemical effects of the mutations directly correlate with contrasting effects on channel electrophysiology. A comprehensive model is proposed in which the hH1 IQ motif serves as a molecular switch, coupling the intrinsic and extrinsic calcium sensors.