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Termination of Cardiac Ca²⁺ Sparks

Role of Intra-SR [Ca²⁺], Release Flux, and Intra-SR Ca²⁺ Diffusion

From the Department of Molecular Biophysics and Physiology (A.V.Z., L.A.B.), Rush University Medical Center, Chicago, Ill; and Department of Pharmacology (E.P., D.M.B.), University of California, Davis.

Correspondence to Lothar A. Blatter, Department of Molecular Biophysics and Physiology, Rush University, 1750 W Harrison St, Chicago, IL 60612. E-mail Lothar_Blatter{at}rush.edu

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.

Key Words: heart • sarcoplasmic reticulum • Ca²⁺ sparks • Ca²⁺-induced Ca²⁺ release • ryanodine receptor

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