Linking Calsequestrin to Lumenal Control of SR Ca 2+ Release

Abstract

See related article, pages 617–626 The heart, beating constantly over the course of the human lifetime, operates continuously through the process of excitation-contraction coupling. Initiated by a depolarizing influx of Na, a small Ca2+ flux across the sarcolemma causes a large release of Ca2+ from the sarcoplasmic reticulum (SR). Release of this Ca2+ takes place via the ryanodine receptor (RyR), a Ca2+ channel within the SR membrane which is gated by cytoplasmic Ca2+ ([Ca2+]i).1 This gating takes place to a small but significant extent even at the relatively low [Ca2+]i found during diastole within the myocyte (SR Ca2+ leak). Among the striking features of this SR Ca2+ release is its steep nonlinear dependence on the total concentration of Ca2+ found in the lumen of the SR ([Ca2+]SRT). The degree of release at diastolic [Ca2+]i is very low when the [Ca2+]SRT is approximately 50% of the level usually found in an isolated cardiac myocyte.2 However, it increases dramatically as [Ca2+]SRT increases toward its normal level. Of special interest is the effect of SR [Ca2+] on the SR Ca2+ leak through the RyR. In the cardiac ventricular myocyte, this leak takes place just under the sarcolemmal membrane, the location of many proteins whose effects are regulated by Ca2+. The magnitude of SR Ca2+ leak may alter the activity of these proteins. Among the candidate proteins which may be affected by the subsarocolemmal Ca2+ is the sodium-calcium exchanger (NCX). This may be particularly relevant in cells from hearts undergoing chronic failure because the myocytes from these heart have a higher leak rate than normal.2 These …