J Mol Cell Cardiol 34, 941950 (2002) doi:10.1006/jmcc.2002.2032, available online at http://www.idealibrary.com on 1 Calcium Cycling Local Ca 2 Signaling and EC Coupling in Heart: Ca 2 Sparks and the Regulation of the [Ca 2 ] i Transient Silvia Guatimosim 1 , Keith Dilly 1 , L. Fernando Santana 2 , M. Saleet Jafri 3 , Eric A. Sobie 1 and W. J. Lederer 1, * 1 Medical Biotechnology Center and Institute of Molecular Cardiology, University of Maryland Biotechnology Institute, 725 W. Lombard Street, Baltimore, MD 21201, USA; 2 Department of Physiology and Biophysics, University of Washington, School of Medicine, Seattle, WA 98102, USA, and 3 Department of Mathematics, University of Dallas, Dallas, TX, USA (Received 11 February 2002, accepted for publication 29 April 2002) S. GUATIMOSIM, K. DILLY, L. F. SANTANA, M. S. JAFRI, E. A. SOBIE AND W. J. LEDERER. Local Ca 2 Signaling and EC Coupling in Heart: Ca 2 Sparks and the Regulation of the [Ca 2 ] i Transient. Journal of Molecular and Cellular cardiology (2002) 34, 941950. The elementary event of Ca 2 release in heart is the Ca 2 spark. It occurs at a low rate during diastole, activated only by the low cytosolic [Ca 2 ] i . Synchronized activation of many sparks is due to the high local [Ca 2 ] i in the region surrounding the sarcoplasmic reticulum (SR) Ca 2 release channels and is responsible for the systolic [Ca 2 ] i transient. The biophysical basis of this calcium signaling is discussed. Attention is placed on the local organization of the ryanodine receptors (SR Ca 2 release channels, RyRs) and the other proteins that underlie and modulate excitationcontraction (EC) coupling. A brief review of speci®c elements that regulate SR Ca 2 release (including SR lumenal Ca 2 and coupled gating of RyRs) is presented. Finally integrative calcium signaling in heart is presented in the context of normal heart function and heart failure. # 2002 Elsevier Science Ltd. All rights reserved. KEY WORDS: Calcium sparks; Sparks; DHPR; Ca 2 channels; Potassium channels; FK binding proteins; Coupled gating; EC coupling; Excitationcontraction coupling; Arrhythmia; Action potential prolongation; Cardiac ventricular myocytes; Heart failure. Introduction Calcium signaling in heart General A time-dependent increase in intracellular Ca 2 concentration (``[Ca 2 ] i transient'') occurs with each heart beat and is responsible for activating contraction. The [Ca 2 ] i transient is activated by the cardiac action potential (AP) and spreads through the heart as the AP is propagated. There are two components of the [Ca 2 ] i transient: (i) the Ca 2 in¯ux and (ii) the Ca 2 release. The depolarization of the AP activates Ca 2 channels (primarily L-type) and results in in¯ux of Ca 2 . The increase in [Ca 2 ] i activates Ca 2 release channels in the sarcoplasmic reticulum (SR), identi®ed as ryanodine receptors (RyRs), by the process known as Ca 2 -induced Ca 2 -release (CICR). While Ca 2 release is largely controlled at the local (subcellular) level as discussed below, the [Ca 2 ] i transient that controls contraction is largely a global (cell-wide) process. The magnitude of the [Ca 2 ] i transient and its kinetics are modulated by many factors (see below). Some of these factors act primarily on the Ca 2 in¯ux components, while *Please address all correspondence to: W. J. Lederer, Tel: 410-706-8181; Fax: 253-660-4449; E-mail: lederer@umbi.umd.edu 00222828/02/080941  10 $35.00/0 # 2002 Elsevier Science Ltd. All rights reserved.