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: 13.77). 09/2010; 120(10):3508-19. DOI: 10.1172/JCI43621
Source: PubMed

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 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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    • "Residue Kinase SSI I NaL Comments Reference S516 CaMKII ← ↔ Ashpole et al. (2012) T594 CaMKII ← ↔ Ashpole et al. (2012) S571 CaMKII ← ↑ Basally phosphorylated by MS Hund et al. (2010), Koval et al. (2012), Marionneau et al. (2012) "
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    • "Application of TatCN21 on neurons inhibits the kinase but also reduces the level of kinase at synaptic sites (Sanhueza et al., 2011), decreases clustering in dendrites, and produces aggregates with polyribosomes (Tao- Cheng et al., 2013). CaMKIINtides also block interaction with densin (Jiao et al., 2011) and Cav2.1 calcium channels (Magupalli et al., 2013) and possibly with β IV -spectrin and other proteins (Hund et al., 2010). Finally, the biological function of CaMKIIN is not fully understood and it may directly affect cellular pathways unrelated to CaMKII inhibition or interference with its translocation. "
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    • "However, where and under what conditions hyperphosphorylation of Tau occurs remains unknown . Interestingly, several kinases have been reported to be enriched at the AIS including CK2 and CAMKII (Bréchet et al, 2008; Hund et al, 2010), but so far no phosphatase has been reported at the AIS. Schafer et al (2009) recently showed that neuronal injury leads to irreversible loss of the AIS and neuronal polarity. "
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