Pathways for CaMKII activation in disease

Abstract

The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) has emerged as an interesting proarrhythmic and procardiomyopathic signaling molecule with therapeutic potential. The importance of this growing body of evidence showing that CaMKII plays a central role in myocardial disease is evidenced, in part, by this thematic series dedicated to CaMKII. The first reports that CaMKII could participate in ion channel biology in heart were in 1994 when separate papers from the Anderson, Bers and Lakatta groups identified CaMKII as a signal that was important for L-type Ca2+ current (ICa) facilitation. CaMKII induces L-type Ca2+ channels to enter a highly active gating mode, characterized by long and frequent openings,1 which can underlie arrhythmia-inducing afterdepolarizations (the topic of xyz Pitt). I became interested in the potential for CaMKII to act as a proarrhythmic, feed-forward, signal to L-type Ca2+ channels when I was a trainee in cardiovascular medicine and electrophysiology at Stanford. I was fortunate to develop a collaboration with Howard Schulman, who discovered CaMKII when he was a post-doctoral fellow in the laboratory of Paul Greengard in 1978.2 Initial investigations of CaMKII were focused on its role in non-cardiac tissue, particularly by neuroscientists but, in my opinion, the current best understood role of CaMKII as a disease signal is in the cardiovascular system. Our group was the first to identify CaMKII as a proarrhythmic signaling molecule.3 But since the time of these early reports, work from many laboratories represented in this series, and from others, has shown that CaMKII promotes pathological membrane excitability, hypertrophic transcription, activates cell death machinery and disturbs intracellular Ca2+ homeostasis. The diversity of these processes sparked the realization that CaMKII acts as a master regulator of cellular processes that are intimately involved in heart failure and arrhythmias. It may be that the apparent vulnerability in the design of the CaMKII pathway is a natural consequence of the multiple downstream CaMKII targets and the core physiological roles of CaMKII in myocardium. For example, by targeting sarcolemmal ion channels and intracellular Ca2+ homeostatic proteins, CaMKII is positioned to serve as a physiological interface between membrane excitability and sarcoplasmic reticulum Ca2+ release, two processes that are essential for excitation-contraction coupling.4 However, this interface is also a hotspot for linking pathological membrane excitability (i.e. arrhythmias) and contractile dysfunction (i.e. heart failure).