Under continuous activation by cytosolic Ca2+, RyR2s periodically cycle between open and deactivated states due to luminal Ca2+ effects, a process potentially mediated by CASQ2.
Under continuous activation by cytosolic Ca2+, RyR2s periodically cycle between open and deactivated states due to luminal Ca2+ effects, with deactivation potentially mediated by CASQ2.
During the cardiac cycle, the release of Ca(2+) from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR2) channel complex is controlled by the levels of cytosolic and luminal Ca(2+) and alterations in these regulatory processes have been implicated in cardiac disease including arrhythmia. To better understand the mechanisms of regulation of SR Ca(2+) release by Ca(2+) on both sides of the SR membrane, we investigated SR Ca(2+) release in a wide range of cytosolic Ca(2+) concentrations (Ca(2+)(cyt); 1-100 microm) in permeabilized canine ventricular myocytes by monitoring Ca(2+) inside the SR (Ca(2+)(SR)). Exposing myocytes to activating Ca(2+)(cyt) resulted in spontaneous oscillations of Ca(2+)(SR) due to periodic opening and closing of the RyR2s. Elevating Ca(2+)(cyt) (up to 10 microm) increased the frequency of Ca(2+)(SR) oscillations; however at higher Ca(2+)(cyt) (>50 microm) the oscillations diminished due to RyR2s staying perpetually open, resulting in depleted SR. Ablation of cardiac calsequestrin (CASQ2) altered the Ca(2+)(cyt) dependence of Ca(2+) release oscillations such that oscillations were highly frequent at low Ca(2+)(cyt) (100 nm) but became diminished at moderate Ca(2+)(cyt) (10 microm), as determined in myocytes from calsequestrin-null versus wild-type mice. Our results suggest that under conditions of continuous activation by cytosolic Ca(2+), RyR2s can periodically cycle between open and deactivated states due to effects of luminal Ca(2+). Deactivation at reduced Ca(2+)SR appears to involve reduction of sensitivity to cytosolic Ca(2+) and might be mediated by CASQ2. Inactivation by cytosolic Ca(2+) plays no detectable role in controlling SR Ca(2+) release.
Stevens et al. (Tue,) reported a other. Varying cytosolic Ca(2+) concentrations vs. Calsequestrin-null versus wild-type mice was evaluated on SR Ca(2+) release oscillations. Under continuous activation by cytosolic Ca2+, RyR2s periodically cycle between open and deactivated states due to luminal Ca2+ effects, a process potentially mediated by CASQ2.
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