Lu Ling, Timofeyev Valeriy, Li Ning, Rafizadeh Sassan, Singapuri Anil, Harris Todd R, Chiamvimonvat Nipavan
Division of Cardiovascular Medicine, Department of Medicine, University of California, Davis, CA 95616, USA.
Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18402-7. doi: 10.1073/pnas.0908207106. Epub 2009 Oct 8.
The importance of proper ion channel trafficking is underpinned by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface. Conceptually, it is reasonable to suggest that the function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane, which is determined jointly by the secretory and endocytic pathways. Yet the precise mechanisms of the entire ion channel trafficking pathway remain unknown. Here, we directly demonstrate that proper membrane localization of a small-conductance Ca(2+)-activated K(+) channel (SK2 or K(Ca)2.2) is dependent on its interacting protein, alpha-actinin2, a major F-actin crosslinking protein. SK2 channel localization on the cell-surface membrane is dynamically regulated, and one of the critical steps includes the process of cytoskeletal anchoring of SK2 channel by its interacting protein, alpha-actinin2, as well as endocytic recycling via early endosome back to the cell membrane. Consequently, alteration of these components of SK2 channel recycling results in profound changes in channel surface expression. The importance of our findings may transcend the area of K(+) channels, given that similar cytoskeletal interaction and anchoring may be critical for the membrane localization of other ion channels in neurons and other excitable cells.
许多与通道相关的遗传性疾病都表明了正确的离子通道运输的重要性，这些疾病的缺陷与无法到达细胞表面有关。从概念上讲，有理由认为离子通道的功能关键取决于其在亚细胞中的精确定位以及细胞表面膜上通道蛋白的数量，而这是由分泌途径和内吞途径共同决定的。然而，整个离子通道运输途径的确切机制仍然未知。在这里，我们直接证明了小电导钙激活钾通道（SK2或K(Ca)2.2）的正确膜定位取决于其相互作用蛋白α-辅肌动蛋白2，一种主要的F-肌动蛋白交联蛋白。SK2通道在细胞表面膜上的定位是动态调节的，其中一个关键步骤包括其相互作用蛋白α-辅肌动蛋白2对SK2通道进行细胞骨架锚定的过程，以及通过早期内体回到细胞膜的内吞再循环过程。因此，SK2通道再循环这些成分的改变会导致通道表面表达的深刻变化。鉴于类似的细胞骨架相互作用和锚定可能对神经元和其他可兴奋细胞中其他离子通道的膜定位至关重要，我们的发现的重要性可能超越钾通道领域。
