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

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 09/2010; 120(10):3508-19. DOI: 10.1172/JCI43621
Source: PubMed


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.

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Available from: Matthew Rasband, Sep 03, 2014
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    • "Calmodulin-dependent kinase (CaMKII), a serine/threonine kinase with diverse regulatory functions in ion transporter function, transcription, and cell death, is targeted to the AIS through interaction with the CaMKII-binding motif of β-IV-spectrin. A C-terminal truncation of β-IV-spectrin resulted in aberrant targeting of CaMKII, while localization of ankyrin-G and spectrin at the AIS was normal (59). Cyclin-dependent kinase (Cdk)-dependent phosphorylation of the Kv2β subunit inhibits the interaction of Kv2β with microtubule proteins. "
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    • "CaMKII is an established regulator of the myocardial Na+ current (INa), and simultaneously potentiates late INa (INaL) while decreasing channel availability (Herren et al., 2013). While the specific phosphorylations required for these effects remain debated, available evidence suggests that either or both Ser-571 and Ser-516 may be key sites (Hund et al., 2010; Ashpole et al., 2012; Koval et al., 2012; Herren et al., 2013), and it is generally agreed that the I-II intracellular linker is the critical phosphoregulatory domain. "
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