Termination of Ca$^2+$ release by a local inactivation of ryanodine receptors in cardiac myocytes.
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Proc. Natl. Acad. Sci. U. S. A. 95 (25): 15096--15101 (декабря 1998)

In heart, a robust regulatory mechanism is required to counteract the regenerative Ca$^2+$-induced Ca$^2+$ release from the sarcoplasmic reticulum. Several mechanisms, including inactivation, adaptation, and stochastic closing of ryanodine receptors (RyRs) have been proposed, but no conclusive evidence has yet been provided. We probed the termination process of Ca$^2+$ release by using a technique of imaging local Ca$^2+$ release, or "Ca$^2+$ spikes", at subcellular sites; and we tracked the kinetics of Ca$^2+$ release triggered by L-type Ca$^2+$ channels. At 0 mV, Ca$^2+$ release occurred and terminated within 40 ms after the onset of clamp pulses (0 mV). Increasing the open-duration and promoting the reopenings of Ca$^2+$ channels with the Ca$^2+$ channel agonist, FPL64176, did not prolong or trigger secondary Ca$^2+$ spikes, even though two-thirds of the sarcoplasmic reticulum Ca$^2+$ remained available for release. Latency of Ca$^2+$ spikes coincided with the first openings but not with the reopenings of L-type Ca$^2+$ channels. After an initial maximal release, even a multi-fold increase in unitary Ca$^2+$ current induced by a hyperpolarization to -120 mV failed to trigger additional release, indicating absolute refractoriness of RyRs. When the release was submaximal (e.g., at +30 mV), tail currents did activate additional Ca$^2+$ spikes; confocal images revealed that they originated from RyRs unfired during depolarization. These results indicate that Ca$^2+$ release is terminated primarily by a highly localized, use-dependent inactivation of RyRs but not by the stochastic closing or adaptation of RyRs in intact ventricular myocytes.
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