A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium

Male 0301 basic medicine 0303 health sciences Ryanodine Receptor Calcium Release Channel Middle Aged Cyclic AMP-Dependent Protein Kinases Recombinant Proteins 3. Good health Tacrolimus Binding Proteins Electrocardiography 03 medical and health sciences Catecholamines Cytosol Death, Sudden, Cardiac HEK293 Cells Phenotype Diastole Mutagenesis, Site-Directed Tachycardia, Ventricular Humans Point Mutation Calcium Ion Channel Gating
DOI: 10.1161/circresaha.111.244970 Publication Date: 2011-06-10T09:07:57Z
ABSTRACT
Rationale: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal arrhythmias young individuals during β-adrenergic stimulation. Objective: This study sought determine effects of a novel RyR2-G230C mutation and whether this RyR2-P2328S alter sensitivity channel luminal calcium (Ca 2+ ). Methods Results: Functional characterizations recombinant human channels were performed under conditions mimicking stress. Human mutant generated by site-directed mutagenesis heterologously expressed HEK293 cells together with calstabin2. measured examine regulation cytosolic versus sarcoplasmic reticulum Ca . A 50-year-old white man repeated syncopal episodes after exercise had arrest harbored RyR2-G230C. cAMP-dependent protein kinase–phosphorylated exhibited significantly higher open probability at diastolic concentrations, associated depletion The sensitivities WT-like. Conclusions: exhibits similar biophysical defects compared previously characterized CPVT mutations: decreased binding stabilizing subunit calstabin2 leftward shift dependence for activation that simulate exercise, consistent “leaky” channel. Both exhibit normal activation. Thus, leak caused reduced levels is common mechanism underlying CPVT.
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