Toward a hierarchy of mechanisms in CaMKII-mediated arrhythmia

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.

Keywords: CaMKII; afterdepolarizations; arrhythmias; cardiovascular diseases; ryanodine receptor.

FIGURE 1

CaMKII regulation of cardiomyocyte electrophysiology and Ca²⁺ handling. CaMKII exerts acute (black) and transcriptional (blue) regulation ([10]-Wu et al., 2006; [11]-Backs et al., 2006) of many key proteins in cardiac electrophysiology and calcium handling. Acute phosphorylation of LCCs by CaMKII potentiates I_CaL and slows inactivation ([1]-Yuan and Bers, 1994). Transcriptional effects are less established but likely downregulate channel expression ([2]-Ronkainen et al., 2011). Phosphorylation of RyR2 by CaMKII promotes Ca²⁺ release from the SR and is implicated in many proarrhythmic contexts ([3]-Witcher et al., 1991; [4]-Wehrens et al., 2004). Available data suggest CaMKII transcriptional regulation promotes Ca²⁺ extrusion from the cell by increasing NCX expression and decreasing SERCA ([6]-Mani et al., 2010; [5]-Lu et al., 2011). I_to and I_K1 are enhanced by acute CaMKII phosphorylation ([7]-Li et al., 2006), and transcriptional downregulation of these currents is a well-established effect of long term CaMKII activity. This reduces repolarization reserve and may destabilize resting membrane potential ([8]-Wagner et al., 2009). Acute regulatory effects of CaMKII on Na_V1.5 enhance inactivation, decrease availability and potentiate I_NaL, but again any transcriptional regulation is unclear ([9]-Wagner et al., 2006). Acute phosphorylation of PLN disinhibits SERCA and enhances SR Ca²⁺ reuptake ([12]-Karczewski et al., 1997).

FIGURE 2

CaMKII positive feedback mechanisms involved in cardiac disease. As a Ca²⁺ regulated kinase, CaMKII is sensitive to any physiological mechanism that alters intracellular Ca²⁺ cycling. Many of its own catalytic actions result in such alterations, and two gain-of-function effects that create positive feedback by enhancing Ca²⁺ cycling occur at I_CaL (left) and I_Na (right). CaMKII regulation of I_Na is thought to increase intracellular Na⁺ via enhanced late I_Na, which in turn reduces the thermodynamic potential for Ca²⁺ extrusion via NCX. CaMKII regulation of I_CaL more directly enhances Ca²⁺ cycling by increasing Ca²⁺ influx through slightly elevated peak current and slowed inactivation.

FIGURE 3

Mechanisms of CaMKII-mediated afterdepolarizations. (A) Pathological CaMKII regulation can trigger diastolic SR Ca²⁺ release resulting in electrogenic Ca²⁺ extrusion by NCX and DADs (red arrows). This results from pro-arrhythmic CaMKII regulation at multiple target proteins, which together drive 3 mechanisms through which CaMKII promotes SCR. First, CaMKII elicits gain-of-function effects at I_CaL and SERCA (via PLN-mediated disinhibition), thereby increasing Ca²⁺ influx and resulting in Ca²⁺ overload (mechanism 1, blue arrows). Second, CaMKII hyper-phosphorylation of Na_V1.5 can elevate intracellular Na⁺ resulting in Na⁺-induced Ca²⁺-overload by decreasing Ca²⁺ efflux through NCX (mechanism 2, black arrows). Third, CaMKII directly phosphorylates RyR2, which has been shown to promote SCR and has been strongly implicated in a number of different models of arrhythmogenic disease (mechanism 3, red arrow). (B) CaMKII phosphorylation of depolarizing currents reduces repolarization reserve and promotes EADs (red arrows) in certain disease contexts. Altered LCC gating due to CaMKII hyper-activity can elicit EADs by increasing and prolonging I_CaL (mechanism 4, blue arrows). Na_V1.5 phosphorylation increases I_NaL and may lead to non-equilibrium reactivation of I_Na (mechanism 5, black arrows), both of which can trigger EADs.