A β_IV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

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Abstract

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 βIV-spectrin as a multifunctional regulatory platform for Na+ channels in mice. We found that βIV-spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant βIV-spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na+ channels, via direct phosphorylation by βIV-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.

Authors

Thomas J. Hund, Olha M. Koval, Jingdong Li, Patrick J. Wright, Lan Qian, Jedidiah S. Snyder, Hjalti Gudmundsson, Crystal F. Kline, Nathan P. Davidson, Natalia Cardona, Matthew N. Rasband, Mark E. Anderson, Peter J. Mohler