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

Abstract

Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltagegated Na + channels underlie cellular excitability and control neuronal communication, cardiac excitationcontraction 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.

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

“…Therefore, we surmised that the differences in the rate dependence of myocardial conduction and excitability are likely related to differences in Na channel activity rather than expression. In recent years, studies have focused on the intricate regulation of Nav1.5 activity by CaMKII,24, 25, 26, 27 a key calcium‐dependent kinase that is activated in MI. In particular, CAMKII activation was shown to modulate Na channel recovery from inactivation 27.…”

“…CAMKII, a calcium‐sensitive kinase that is activated post‐MI, regulates Na channel activity in a rate‐dependent manner 24, 25, 27. In particular, CAMKII‐dependent phosphorylation of Nav1.5 alters I Na gating by reducing current availability at higher pacing rates 27.…”

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Our new findings together with our previous work8 indicate that β IV ‐spectrin associates with TREK‐1 and is essential for its proper membrane targeting in myocytes throughout the heart. The precise nature of this association remains to be determined, but it is interesting to speculate that spectrin may target a distinct subpopulation of TREK‐1 with unique localization and regulatory properties, similar to its involvement in Ca 2+ /calmodulin‐dependent protein kinase II–dependent regulation of the cardiac voltage‐gated Na + channel Na v 1.5 24, 29, 43…”

β IV -Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

“…This motif is present in a handful of CaMKII-associated proteins including the L-type Ca 2+ channel beta subunit (β 2a ) and the NR2B receptor (9). Given the lack of data on β IV -spectrin function in the islet, we hypothesized that β IVspectrin may function in the pancreas to control CaMKII targeting and expression, similar to observed roles in myocytes (10).…”