Molecular coupling of a Ca2+-activated K+ channel to L-type Ca2+ channels via α-actinin2
Molecular coupling of a Ca2+-activated K+ channel to L-type Ca2+ channels via α-actinin2
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DOI：
10.1161/01.res.0000253095.44186.72
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发表时间：
2007-01-05
影响因子：
20.1
通讯作者：
Chiamvimonvat, Nipavan
中科院分区：
文献类型：
--
作者：
Lu, Ling;Zhang, Qian;Chiamvimonvat, Nipavan
已知细胞骨架蛋白塑造细胞的结构架构。然而，它们作为连接不同离子通道的功能串扰的桥梁的作用是未知的。在这里，我们证明了小电导Ca 2+激活的K+通道（SK 2通道），存在于各种细胞中，在那里它们整合细胞内Ca 2+浓度[Ca-i（2+）]的变化与K+电导和膜电位的变化，与L型Ca 2+通道; Ca（v）1.3和Ca（v）1.2通过物理桥，在心肌细胞中的α-辅肌动蛋白2。SK2通道不与L型Ca 2+通道发生物理相互作用，而是通过与α-辅肌动蛋白2细胞骨架蛋白相互作用共定位。SK2通道与α-辅肌动蛋白2的结合使通道定位于外源性钙离子的进入，从而调节通道功能。此外，我们证明了心房肌细胞中SK 2通道的功能严重依赖于Cav1.3 Ca 2+通道的正常表达。Cav1.3通道的缺失可导致SK2通道功能异常，复极延长，房性心律失常。我们的研究提供了深入了解SK2通道与电压门控Ca ~（2+）通道耦合的分子机制，并代表了第一个报告连接2种不同类型的离子通道通过细胞骨架蛋白的耦合。
Cytoskeletal proteins are known to sculpt the structural architecture of cells. However, their role as bridges linking the functional crosstalk of different ion channels is unknown. Here, we demonstrate that a small conductance Ca2+-activated K+ channels (SK2 channel), present in a variety of cells, where they integrate changes in intracellular Ca2+ concentration [Ca-i(2+)] with changes in K+ conductance and membrane potential, associate with L-type Ca2+ channels; Ca(v)1.3 and Ca(v)1.2 through a physical bridge, alpha-actinin2 in cardiac myocytes. SK2 channels do not physically interact with L-type Ca2+ channels, instead, the 2 channels colocalize via their interaction with alpha-actinin2 cytoskeletal protein. The association of SK2 channel with alpha-actinin2 localizes the channel to the entry of external Ca2+ source, which regulate the channel function. Furthermore, we demonstrated that the functions of SK2 channels in atrial myocytes are critically dependent on the normal expression of Cav1.3 Ca2+ channels. Null deletion of Cav1.3 channel results in abnormal function of SK2 channel and prolongation of repolarization and atrial arrhythmias. Our study provides insight into the molecular mechanisms of the coupling of SK2 channel with voltage-gated Ca2+ channel, and represents the first report linking the coupling of 2 different types of ion channels via cytoskeletal proteins.