Impaired calcium-calmodulin-dependent inactivation of Cav1.2 contributes to loss of sarcoplasmic reticulum calcium release refractoriness in mice lacking calsequestrin 2

Journal of Molecular and Cellular Cardiology
Dmytro O KryshtalBjörn C Knollmann

Abstract

In cardiac muscle, Ca(2+) release from sarcoplasmic reticulum (SR) is reduced with successively shorter coupling intervals of premature stimuli, a phenomenon known as SR Ca(2+) release refractoriness. We recently reported that the SR luminal Ca(2+) binding protein calsequestrin 2 (Casq2) contributes to release refractoriness in intact mouse hearts, but the underlying mechanisms remain unclear. Here, we further investigate the mechanisms responsible for physiological release refractoriness. Gene-targeted ablation of Casq2 (Casq2 KO) abolished SR Ca(2+) release refractoriness in isolated mouse ventricular myocytes. Surprisingly, impaired Ca(2+)-dependent inactivation of L-type Ca(2+) current (ICa), which is responsible for triggering SR Ca(2+) release, significantly contributed to loss of Ca(2+) release refractoriness in Casq2 KO myocytes. Recovery from Ca(2+)-dependent inactivation of ICa was significantly accelerated in Casq2 KO compared to wild-type (WT) myocytes. In contrast, voltage-dependent inactivation measured by using Ba(2+) as charge carrier was not significantly different between WT and Casq2 KO myocytes. Ca(2+)-dependent inactivation of ICa was normalized by intracellular dialysis of excess apo-CaM (20 μM), which als...Continue Reading

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