[HTML][HTML] A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

TJ Hund, OM Koval, J Li, PJ Wright… - The Journal of …, 2010 - Am Soc Clin Investig
TJ Hund, OM Koval, J Li, PJ Wright, L Qian, JS Snyder, H Gudmundsson, CF Kline…
The Journal of clinical investigation, 2010Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation