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Mechanism of Calmodulin Inhibition of Cardiac Sarcoplasmic Reticulum Ca²⁺ Release Channel (Ryanodine Receptor)

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7260

Correspondence: Address reprint requests to Gerhard Meissner, Tel.: 919-966-5021; Fax: 919-966-2852; E-mail: meissner{at}med.unc.edu.

The functional effects of calmodulin (CaM) on single cardiac sarcoplasmic reticulum Ca²⁺ release channels (ryanodine receptors) (RyR2s) were determined in the presence of two endogenous channel effectors, MgATP and reduced glutathione, using the planar lipid bilayer method. Single-channel activities, number of events, and open and close times were determined at varying cytosolic Ca²⁺ concentrations. CaM reduced channel open probability at <10 µM Ca²⁺ by decreasing channel events and mean open times and increasing mean close times. At >10 µM Ca²⁺, CaM was less effective in inhibiting RyR2. CaM decreased mean open times but increased channel events, without significantly affecting mean close times. A series of voltage pulses was applied to the bilayer from +50 to -50 mV and from -50 mV to +50 mV to rapidly increase and decrease open channel-mediated sarcoplasmic reticulum lumenal to cytosolic Ca²⁺ fluxes. CaM decreased the duration of the open events after the voltage switch from -50 mV to +50 mV. In parallel experiments, a Ca²⁺-insensitive calmodulin mutant was without effect on RyR2 activity. The results are discussed in terms of a possible role of CaM in the termination of cardiac sarcoplasmic reticulum Ca²⁺ release.

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