Is the ryanodine receptor a target for antiarrhythmic therapy?

In cardiac myocytes, Ca 2 influx and efflux must be in balance to ensure cellular viability, normal contractile function, and a stable heart rhythm. Therefore Ca fluxes between the major cellular compartments and the extracellular space have to adapt to a wide range of changing conditions. Failure to do so can result in Ca overload of the sarcoplasmic reticulum (SR), leading to arrhythmogenic spontaneous release of SR Ca by ryanodine receptors (RyRs). Recently, it was shown that suppressing RyR open probability (Po) was protective in a mouse model of a congenital arrhythmia caused by increased Ca leak from RyRs. It was suggested that such a strategy could be applied more widely to treat patients with common ventricular arrhythmias.1 Is it possible to suppress SR Ca release without jeopardizing contractile function and aggravating Ca overload? In this issue of Circulation Research, Venetucci et al2 answer this question by using the analytic techniques they have used so successfully in the past to examine Ca fluxes and autoregulation in normal cells.3 Their surprising finding is that reducing RyR Po in Ca -overloaded myocytes not only suppresses arrhythmogenic spontaneous Ca release, but also increases the amplitude of the Ca transient while maintaining Ca homeostasis. To fully appreciate this finding, it is essential to review the profile of Ca fluxes under both physiological conditions and during arrhythmogenic events. Under normal conditions, Ca enters the cardiomyocyte at the beginning of each contractile cycle through L-type Ca channels (LCCs) and minimally raises the cytoplasmic Ca concentration. This “trigger calcium” binds to RyRs and induces an even greater release of stored Ca from the SR into the cytoplasm, which causes myofilament contraction. Survival of the cell, as well as relaxation, both depend on the reuptake of 75% of the cytoplasmic Ca by SERCA into the SR.4 Most of the remaining Ca is extruded by the sodium-calcium exchanger (NCX), with minimal amounts of removal by the sarcolemmal Ca pump. The removal of Ca by NCX leaves the cell containing the exact same amount of Ca it started out with.5 Yet the high gain positive feedback system of Ca -induced Ca release in heart muscle poses a challenge for the maintenance of Ca homeostasis. Calcium released from the SR by RyRs could conceivably spread to and activate all of the other RyRs in the cell, resulting in an asynchronous and slow release of SR Ca (eg, a Ca wave) with each action potential. Stern et al6 predicted that synchronous contraction, graded release, and stability required “local control,” using physical separation of individual Ca release units, or couplons.7 The “local-control” theory predicts that an increase in Ca current will recruit more release units and thereby increase global SR Ca release to provide an inotropic response. This theory has been supported by the identification of individual Ca release sites known as Ca sparks.8 Physiologic beta adrenergic stimulation, for example during exercise, increases Ca influx via LCCs and increases SR Ca uptake by SERCA, mainly as a result of G protein–mediated phosphorylation of LCCs and phospholamban.4 NCX activity also increases because of increased binding of Ca to the NCX catalytic site,9 but SERCA still out-competes NCX for Ca and therefore SR Ca content increases. As we discuss below, the increase in SR Ca load may increase the risk of spontaneous Ca release and triggered arrhythmias. Cellular Ca overload is also a hallmark of ATP depletion during myocardial ischemia. Surprisingly, energy deprivation does not decrease SR Ca content.10 How can this be? During the metabolic stress of ischemia, the free energy available for SERCA function eventually declines. These same changes in free energy lead to reduced Ca influx through LCCs,10 reduced RyR Ca sensitivity, and Po and consequently reduced Ca release from the SR.11 If the RyR Po remains reduced while SERCA activity is maintained, Ca overload of the SR may eventually occur. Na gain may further reduce Ca removal by NCX, leaving more Ca to be taken up by SERCA into the SR. As luminal SR Ca content increases, RyR Po will increase,12 a process reinforced by the rise in cytoplasmic Ca . Both of these effects eventually override the inhibitory effects of metabolic stress on the RyR, resulting in spontaneous release of Ca and generation of Ca waves. Ca released into the cytoplasm during a Ca wave is handled by the myocyte in two ways: (1) re-uptake by the SR (assuming SERCA activity remains), and (2) removal from the cell by NCX. Efflux of Ca by NCX generates a transient inward current (ITI), which is capable of bringing Na channels to threshold and producing delayed after-depolarizations or DADs.13 Pogwizd et al14 demonstrated that most ventricular arrhythmias in non-ischemic cardiomyopathy are initiated by non-reentrant mechanisms, exemplified by DADs. And up to 50% of ventricular arrhythmias in ischemic cardiomyopathy may be initiated by after-depolarizations, though the proportions remain controversial.15 Amazingly, despite reductions in SERCA expression and increases in NCX expression, increased catecholamine levels in heart failure lead to SR Ca The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Physiology and Medicine and the Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, Calif. Correspondence to Joshua I. Goldhaber, MD, David Geffen School of Medicine at UCLA, Cardiology, BH-407 CHS, 10833 LeConte Ave, Los Angeles, CA 90095. E-mail [email protected] (Circ Res. 2006;98:1232-1233.) © 2006 American Heart Association, Inc.