Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
J Clin Invest. 2010 Oct;120(10):3508-19. doi: 10.1172/JCI43621. Epub 2010 Sep 27.
Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltage-gated Na(+) channels underlie cellular excitability and control neuronal communication, cardiac excitation-contraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na(+) channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β(IV)-spectrin as a multifunctional regulatory platform for Na(+) channels in mice. We found that β(IV)-spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β(IV)-spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na(+) channels, via direct phosphorylation by β(IV)-spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.
离子通道功能是生命存在的基础。在多细胞动物中，电压门控 Na(+) 通道的协调活动构成了细胞兴奋性，并控制神经元通讯、心脏兴奋-收缩偶联和骨骼肌功能。然而，尽管已经进行了几十年的研究，并将 Na(+) 通道功能障碍与心律失常、癫痫和肌强直联系起来，但对于调节这些蛋白质家族的基本过程几乎没有取得任何进展。在这里，我们已经确定β(IV)-spectrin 是小鼠中 Na(+) 通道的多功能调节平台。我们发现β(IV)-spectrin 将关键的结构和调节蛋白靶向到心脏和大脑中的可兴奋膜。携带突变β(IV)-spectrin 等位基因的动物模型表现出异常的细胞兴奋性和整个动物生理学。此外，我们发现了一种通过β(IV)-spectrin 靶向钙/钙调蛋白依赖性激酶 II（CaMKII）直接磷酸化的 Na(+) 通道调节机制。总的来说，我们的数据定义了一个意想不到但不可或缺的分子平台，它决定了小鼠心脏和大脑中的膜兴奋性。
