How to stop the fire? Control of Ca2+-induced Ca2+ release in cardiac muscle

Cardiac excitation–contraction coupling in higher vertebrates is driven by the process of calcium-induced calcium release (CICR). According to the original hypothesis, an action potential initiates a small Ca2+ influx through plasmalemmal Ca2+ channels which indirectly activates contraction by triggering a much larger Ca2+ release from ryanodine receptors (RyR2s), Ca2+ channels on the sarcoplasmic reticulum (SR). It is believed that upon relaxation, SR Ca2+ release ceases via cytosolic Ca2+-dependent inactivation of RyR2s, which allows resequestration of Ca2+ to the SR by SR Ca2+-ATPase. Thus CICR, where Ca2+ serves as trigger, output and negative regulator, is an inherently unstable process. Accordingly, uncontrollable Ca2+ release is implicated in many hallmark features of cardiac disease; diastolic pro-arrhythmic aftercontractions and/or loss of SR Ca2+ resulting in reduced systolic Ca2+ transients and thereby impaired contractility.