RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca 2+ release (SOICR)

• DOI: 10.1073/pnas.0402388101
• Publication Date: 2004-08-21T01:28:02Z
• Authors: Dawei Jiang; Bailong Xiao; Dongmei Yang; Ruiwu Wang; Philip Choi; Lin Zhang; Heping Cheng; S. R. Wayne Chen
• Keywords: HEK 293 cells; Sudden Death

The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but precise molecular mechanism is unclear. It known that when reticulum store content reaches a critical level, spontaneous occurs, process we refer as store-overload-induced (SOICR). In view well documented arrhythmogenic nature SOICR, characterized effects disease-causing mutations on SOICR human embryonic kidney (HEK)293 cells found that, at elevated extracellular levels, HEK293 expressing displayed manner virtually identical observed cells. Using this cell model, demonstrated VT N4104K, R4496C, N4895D, markedly increased occurrence SOICR. At showed these sensitivity single channels activation by luminal enhanced basal level [3H]ryanodine binding. We conclude mutations, enhancing activation, reduce threshold for turn increases propensity triggered arrhythmia. Abnormal likely contributes commonly various conditions, including heart failure, may represent unifying overload-associated VT.