期刊
CIRCULATION RESEARCH
卷 103, 期 8, 页码 E105-E115出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.183236
关键词
sarcoplasmic reticulum; Ca2+ sparks; Ca2+-induced Ca2+ release; ryanodine receptor
资金
- NIH [HL80101, HL62231, HL30077]
- American Heart Association [AHA0530309Z]
Ca2+ release from cardiac sarcoplasmic reticulum ( SR) via ryanodine receptors ( RyRs) is regulated by dyadic cleft [Ca2+] and intra-SR free [Ca2+] ([Ca2+](SR)). Robust SR Ca2+ release termination is important for stable excitation-contraction coupling, and partial [Ca2+](SR) depletion may contribute to release termination. Here, we investigated the regulation of SR Ca2+ release termination of spontaneous local SR Ca2+ release events (Ca2+ sparks) by [Ca2+](SR), release flux, and intra-SR Ca2+ diffusion. We simultaneously measured Ca2+ sparks and Ca2+ blinks ( localized elementary [Ca2+](SR) depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca2+ loads and release fluxes. Sparks terminated via a [Ca2+](SR)-dependent mechanism at a fixed [Ca2+](SR) depletion threshold independent of the initial [Ca2+](SR) and release flux. Ca2+ blink recovery depended mainly on intra-SR Ca2+ diffusion rather than SR Ca2+ uptake. Therefore, the large variation in Ca2+ blink recovery rates at different release sites occurred because of differences in the degree of release site interconnection within the SR network. When SR release flux was greatly reduced, long-lasting release events occurred from well-connected junctions. These junctions could sustain release because local SR Ca2+ release and [Ca2+] SR refilling reached a balance, preventing [Ca2+] SR from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca2+] SR, indicative of a slower, [Ca2+](SR)-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca2+ release terminates at a fixed [Ca2+] SR termination threshold. Thus, reliable SR Ca2+ release termination depends on tight RyR regulation by [Ca2+](SR).
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