Calcium signaling between sarcolemmal calcium channels and ryanodine receptors in heart cells.
Cardiac excitation-Ca2+ release coupling is, in essence, a tale of two molecules, sarcolemmal voltage-gated L-type Ca2+ channels (LCCs) and intracellular ryanodine receptors (RyRs), communicating via the Ca2+-induced Ca2+ release mechanism. Recent advances have provided a microscopic view of the intermolecular Ca2+ signaling between LCCs and RyRs. In a dyadic junction or a "couplon", LCCs open and close stochastically upon depolarization, delivering a train of high local Ca2+ pulses ("Ca2+ sparklets") to the RyRs in the abutting SR terminal cisternae. Stochastic activation of RyRs discharges "Ca2+ sparks" from different couplons, which summate into global Ca2+ transients. Hence, ignition of Ca2+ sparks by Ca2+ sparklets constitute elementary events of EC coupling. While the sparklet-spark coupling is of low fidelity (at 0 mV, about one out of 50 sparklets triggers a spark under physiological conditions), the high-gain amplification of CICR (approximately 15 at 0 mV) is achieved because of the greater single-channel flux and open time of RyRs and multi-RyR origin of Ca2+ spark. The global stability of CICR is safeguarded by many factors acting in synergy, including physical separation of RyR clusters, sheer Ca2+ gradients around the channel pores, low intrinsic Ca2+ sensitivity of RyRs in vivo, and high cooperativity for the Ca2+-dependent spark activation. The local stability of CICR is insured because of strong, use-dependent inactivation of RyRs, that terminates Ca2+ sparks and confers persistent local SR refractoriness.
Cheng
Heping
H
Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. chengp@grc.nia.nih.gov
Wang
Shi-Qiang
SQ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D015640:Ion Channel Gating; D007700:Kinetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013816:Thermodynamics
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel