[Frontiers in Bioscience 7, d1454-1463, June 1, 2002]


Sandor Györke 1, Inna Györke 1, Valeriy Lukyanenko 1, Dmitriy Terentyev 1, Serge Viatchenko-Karpinski 1, and Theodore F. Wiesner 2

1 Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6551, 2 Department of Chemical Engineering, Texas Tech University, Lubbock, TX


1. Abstract
2. Introduction
3. Ca2+ in the SR
3.1. Total [Ca2+]SR and calsequestrin
3.2. Free [Ca2+]SR
4. Experimental evidence for modulation of the Ca2+ release mechanism by luminal Ca2+
4.1. Cell studies
4.2. Studies in RyRs reconstituted in bilayers
5. Molecular structure of the luminal Ca2+ sensor
6. Functional Implications to normal physiology and disease
6.1. Termination of CICR
6.2. Dynamic control of SR Ca2+ content and release
6.3. Maintained regulation of Ca2+ release
6.4. Generation of Ca2+ waves
6.5. Heart Failure
7. Conclusion
8. Acknowledgments
9. References


The amount of Ca2+ released from the sarcoplasmic reticulum (SR) is a principal determinant of cardiac contractility. Normally, the SR Ca2+ stores are mobilized through the mechanism of Ca2+-induced Ca2+ release (CICR). In this process, Ca2+ enters the cell through plasmalemmal voltage-dependent Ca2+ channels to activate the Ca2+ release channels in the SR membrane. Consequently, the control of Ca2+ release by cytosolic Ca2+ has traditionally been the main focus of cardiac excitation-contraction (EC) coupling research. Evidence obtained recently suggests that SR Ca release is controlled not only by cytosolic Ca2+, but also by Ca2+ in the lumen of the SR. The presence of a luminal Ca2+ sensor regulating release of SR luminal Ca2+ potentially has profound implications for our understanding of EC coupling and intracellular Ca2+ cycling. Here we review evidence, obtained using in situ and in vitro approaches, in support of such a luminal Ca2+ sensor in cardiac muscle. We also discuss the role of control of Ca2+ release channels by luminal Ca2+ in termination and stabilization of CICR, as well as in shaping the response of cardiac myocytes to various inotropic influences and diseased states such as Ca2+ overload and heart failure.