Termination of cardiac Ca2+ sparks: role of intra-SR Ca2+, release flux, and intra-SR Ca2+ diffusion.
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Circ Res 103 (8): e105--e115 (October 2008)

Ca(2+) release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft Ca(2+) and intra-SR free Ca(2+) (Ca(2+)(SR)). Robust SR Ca(2+) release termination is important for stable excitation-contraction coupling, and partial Ca(2+)(SR) depletion may contribute to release termination. Here, we investigated the regulation of SR Ca(2+) release termination of spontaneous local SR Ca(2+) release events (Ca(2+) sparks) by Ca(2+)(SR), release flux, and intra-SR Ca(2+) diffusion. We simultaneously measured Ca(2+) sparks and Ca(2+) blinks (localized elementary Ca(2+)(SR) depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca(2+) loads and release fluxes. Sparks terminated via a Ca(2+)(SR)-dependent mechanism at a fixed Ca(2+)(SR) depletion threshold independent of the initial Ca(2+)(SR) and release flux. Ca(2+) blink recovery depended mainly on intra-SR Ca(2+) diffusion rather than SR Ca(2+) uptake. Therefore, the large variation in Ca(2+) 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 Ca(2+) release and Ca(2+)(SR) refilling reached a balance, preventing Ca(2+)(SR) from depleting to the termination threshold. Prolonged release events eventually terminated at a steady Ca(2+)(SR), indicative of a slower, Ca(2+)(SR)-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca(2+) release terminates at a fixed Ca(2+)(SR) termination threshold. Thus, reliable SR Ca(2+) release termination depends on tight RyR regulation by Ca(2+)(SR).
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