Lu Ling, Zhang Qian, Timofeyev Valeriy, Zhang Zhao, Young J Nilas, Shin Hee-Sup, Knowlton Anne A, Chiamvimonvat Nipavan
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, One Shields Avenue, GBSF 6315, Davis, CA 95616, USA.
Circ Res. 2007 Jan 5;100(1):112-20. doi: 10.1161/01.RES.0000253095.44186.72. Epub 2006 Nov 16.
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 Ca(2+)-activated K(+) channels (SK2 channel), present in a variety of cells, where they integrate changes in intracellular Ca(2+) concentration [Ca(2+)(i)] with changes in K(+) conductance and membrane potential, associate with L-type Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(v)1.3 Ca(2+) channels. Null deletion of Ca(v)1.3 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 Ca(2+) channel, and represents the first report linking the coupling of 2 different types of ion channels via cytoskeletal proteins.
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功能串扰的桥梁的作用尚不清楚。在这里，我们证明了一种小电导钙激活钾通道（SK2通道）存在于多种细胞中，在这些细胞中，它们将细胞内钙浓度[Ca(2+)(i)]的变化与钾电导和膜电位的变化整合在一起，并通过一个物理桥梁——心肌细胞中的α-辅肌动蛋白2与L型钙通道Ca(v)1.3和Ca(v)1.2相关联。SK2通道并不与L型钙通道发生物理相互作用，相反，这两种通道通过与α-辅肌动蛋白2细胞骨架蛋白的相互作用而共定位。SK2通道与α-辅肌动蛋白2的关联将该通道定位到外部钙源的入口处，从而调节通道功能。此外，我们证明了心房肌细胞中SK2通道的功能严重依赖于Ca(v)1.3钙通道的正常表达。Ca(v)1.3通道的无效缺失导致SK2通道功能异常、复极化延长和房性心律失常。我们的研究深入了解了SK2通道与电压门控钙通道偶联的分子机制，并且是通过细胞骨架蛋白连接两种不同类型离子通道偶联的首篇报道。
