Sarcoplasmic reticulum Ca$^2+$ refilling controls recovery from Ca$^2+$-induced Ca$^2+$ release refractoriness in heart muscle.
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Circ. Res. 95 (8): 807--813 (October 2004)

In cardiac muscle Ca$^2+$-induced Ca$^2+$ release (CICR) from the sarcoplasmic reticulum (SR) is initiated by Ca$^2+$ influx via L-type Ca$^2+$ channels. At present, the mechanisms underlying termination of SR Ca$^2+$ release, which are required to ensure stable excitation-contraction coupling cycles, are not precisely known. However, the same mechanism leading to refractoriness of SR Ca$^2+$ release could also be responsible for the termination of CICR. To examine the refractoriness of SR Ca$^2+$ release, we analyzed Na$^+$-Ca$^2+$ exchange currents reflecting cytosolic Ca$^2+$ signals induced by UV-laser flash-photolysis of caged Ca$^2+$. Pairs of UV flashes were applied at various intervals to examine the time course of recovery from CICR refractoriness. In cardiomyocytes isolated from guinea-pigs and mice, beta-adrenergic stimulation with isoproterenol-accelerated recovery from refractoriness by approximately 2-fold. Application of cyclopiazonic acid at moderate concentrations (<10 micromol/L) slowed down recovery from refractoriness in a dose-dependent manner. Compared with cells from wild-type littermates, those from phospholamban knockout (PLB-KO) mice exhibited almost 5-fold accelerated recovery from refractoriness. Our results suggest that SR Ca$^2+$ refilling mediated by the SR Ca$^2+$-pump corresponds to the rate-limiting step for recovery from CICR refractoriness. Thus, the Ca$^2+$ sensitivity of CICR appears to be regulated by SR Ca$^2+$ content, possibly resulting from a change in the steady-state Ca$^2+$ sensitivity and in the gating kinetics of the SR Ca$^2+$ release channels (ryanodine receptors). During Ca$^2+$ release, the concomitant reduction in Ca$^2+$ sensitivity of the ryanodine receptors might also underlie Ca$^2+$ spark termination by deactivation.
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