crosstalk between mitochondrial and sarcoplasmic reticulum ca2+ cycling modulates cardiac pacemaker cell automaticity相声在线粒体和肌浆网ca2 +循环调节心脏起搏器细胞自动性.pdfVIP

Crosstalk between Mitochondrial and Sarcoplasmic Reticulum Ca2+ Cycling Modulates Cardiac Pacemaker Cell Automaticity Yael Yaniv, Harold A. Spurgeon, Alexey E. Lyashkov, Dongmei Yang, Bruce D. Ziman, Victor A. Maltsev, Edward G. Lakatta* Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America Abstract Background: Mitochondria dynamically buffer cytosolic Ca2+ in cardiac ventricular cells and this affects the Ca2+ load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca2+ releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na+-Ca2+ exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP). Objective: To determine if mitochondrial Ca2+ (Ca2+m), cytosolic Ca2+ (Ca2+c)-SR-Ca2+ crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity. Results: Inhibition of mitochondrial Ca2+ influx into (Ru360) or Ca2+ efflux from (CGP-37157) decreased [Ca2+]m to 80 68% control or increased [Ca2+]m to 119 67% control, respectively. Concurrent with inhibition of mitochondrial Ca2+ influx or efflux, the SR Ca2+ load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca2+ signal were highly correlated with the change in the SR Ca2+ load (r2 = 0.97). Changes in the spontaneous AP cycle length (Ru360, 11161% control; CGP-37157, 8962% control) in response to changes in [Ca2+]m were predicted by concurrent changes in LCR period (r