Published online before print October 20, 2005, doi: 10.1161/01.RES.0000192146.85173.4b
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© 2005 American Heart Association, Inc.
Cellular Biology |
Enhanced Store Overload–Induced Ca2+ Release and Channel Sensitivity to Luminal Ca2+ Activation Are Common Defects of RyR2 Mutations Linked to Ventricular Tachycardia and Sudden Death
From the Cardiovascular Research Group, Departments of Physiology and Biophysics, and of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada.
Correspondence to Dr S.R. Wayne Chen, University of Calgary, Department of Physiology and Biophysics, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. E-mail swchen{at}ucalgary.ca
Ventricular tachycardia (VT) is the leading cause of sudden death, and the cardiac ryanodine receptor (RyR2) is emerging as an important focus in its pathogenesis. RyR2 mutations have been linked to VT and sudden death, but their precise impacts on channel function remain largely undefined and controversial. We have previously shown that several disease-linked RyR2 mutations in the C-terminal region enhance the sensitivity of the channel to activation by luminal Ca2+. Cells expressing these RyR2 mutants display an increased propensity for spontaneous Ca2+ release under conditions of store Ca2+ overload, a process we referred to as store overload–induced Ca2+ release (SOICR). To determine whether common defects exist in disease-linked RyR2 mutations, we characterized 6 more RyR2 mutations from different regions of the channel. Stable inducible HEK293 cell lines expressing Q4201R and I4867M from the C-terminal region, S2246L and R2474S from the central region, and R176Q(T2504M) and L433P from the N-terminal region were generated. All of these cell lines display an enhanced propensity for SOICR. HL-1 cardiac cells transfected with disease-linked RyR2 mutations also exhibit increased SOICR activity. Single channel analyses reveal that disease-linked RyR2 mutations primarily increase the channel sensitivity to luminal, but not to cytosolic, Ca2+ activation. Moreover, the Ca2+ dependence of [3H]ryanodine binding to RyR2 wild type and mutants is similar. In contrast to previous reports, we found no evidence that disease-linked RyR2 mutations alter the FKBP12.6–RyR2 interaction. Our data indicate that enhanced SOICR activity and luminal Ca2+ activation represent common defects of RyR2 mutations associated with VT and sudden death. A mechanistic model for CPVT/ARVD2 is proposed.
Key Words: arrhythmia • Ca2+ handling • Ca2+ transients • heart failure • intracellular calcium • ryanodine receptor • sarcoplasmic reticulum • ventricular tachycardia
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