Toward a hierarchy of mechanisms in CaMKII-mediated arrhythmia.

Kevin P Vincent,Andrew D Mcculloch,Andrew G Edwards

doi:10.3389/fphar.2014.00110

Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1) some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2) these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.

Highlights

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of excitation-contraction coupling in cardiac myocytes
SUMMARY AND CONCLUSION The ability of CaMKII to contribute to arrhythmia in models of cardiac disease that result from widely varying etiologies is testament to the importance of this kinase in the control of cardiac electrophysiology and calcium handling
It suggests that CaMKII exerts its proarrhythmic influence either by regulating some convergent mechanism that is active in all of these diseases, or by regulating a divergent range of proarrhythmic mechanisms, which contribute to differing degrees in each disease

Summary

Introduction

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of excitation-contraction coupling in cardiac myocytes. We suggest that this is a dominant terminal mechanism of CaMKII-mediated arrhythmia, and may explain why experimental manipulation of CaMKII phosphorylation at RyR2 has proven effective in many models of arrhythmogenic disease.

Results

Conclusion