[Frontiers in Bioscience 7, d1697-1711, July 1, 2002]

SARCOPLASMIC RETICULUM CA RELEASE IN INTACT VENTRICULAR MYOCYTES

Donald M. Bers

Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Ca sparks and twitch Ca transients
4. Factors affecting SR Ca release
4.1. Intracellular Free [Ca]
4.2. Intra-SR Free [Ca]
4.3. Turn -off of SR Ca release
4.4. Restitution
4.5. Mg, ATP and pH
4.6. Na/Ca exchange
4.7. Dihydropyridine receptor, Bay K 8644, FPL-64176 and FK-506
4.8. CaMKII, protein kinase A
5. SR Ca CONTENT
5.1. Thermodynamics and Leak vs. Pump-mediated Backflux
5.2. Measurement of SR Ca content
6. Pathophysiological alterations in heart failure
6.1. Reduced SERCA2 and enhanced Na/Ca exchange
6.2. Enhanced SR Ca leak
6.3. Altered E-C coupling
7. Conclusions
8. Acknowledgements
9. References

1. ABSTRACT

Sarcoplasmic reticulum (SR) Ca release in intact ventricular myocytes is the major source of Ca which activates cardiac contraction (although Ca influx makes a non-negligible contribution in most species). The fundamental events of SR Ca release are known as Ca sparks. The twitch Ca transient is composed of ~10,000 Ca sparks occurring in a given cell, and they are synchronized by the action potential and Ca current. Many factors influence SR Ca release amplitude and kinetics, and the focus here is on understanding how these factors work in the intact cellular environment. The intracellular [Ca] ([Ca]i) and intra-SR [Ca] ([Ca]SR) are two of the most important dynamic modulators of SR Ca release. Indeed, while [Ca]i (and Ca current which initiates systolic SR Ca release) is widely acknowledged to be important, it is increasingly clear that [Ca]SR changes dynamically under physiological conditions and that this has very important regulatory effects on the SR Ca release process. While elevation of [Ca]SR obviously increases the driving force and amount of SR Ca available for release, it also increases the fractional release and can be responsible for spontaneous diastolic SR Ca release. These issues are discussed in both normal physiological and pathophysiological contexts.