RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved. OBJECTIVE: Using a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2. METHODS AND RESULTS: The R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect. CONCLUSIONS: A single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2.
RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved. OBJECTIVE: Using a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2. METHODS AND RESULTS: The R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect. CONCLUSIONS: A single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2.
Authors: Dawei Jiang; Bailong Xiao; Dongmei Yang; Ruiwu Wang; Philip Choi; Lin Zhang; Heping Cheng; S R Wayne Chen Journal: Proc Natl Acad Sci U S A Date: 2004-08-20 Impact factor: 11.205
Authors: Marina Cerrone; Barbara Colombi; Massimo Santoro; Marina Raffaele di Barletta; Mario Scelsi; Laura Villani; Carlo Napolitano; Silvia G Priori Journal: Circ Res Date: 2005-05-12 Impact factor: 17.367
Authors: Xander H T Wehrens; Stephan E Lehnart; Fannie Huang; John A Vest; Steven R Reiken; Peter J Mohler; Jie Sun; Silvia Guatimosim; Long Sheng Song; Nora Rosemblit; Jeanine M D'Armiento; Carlo Napolitano; Mirella Memmi; Silvia G Priori; W J Lederer; Andrew R Marks Journal: Cell Date: 2003-06-27 Impact factor: 41.582
Authors: Biyi Chen; Ang Guo; Zhan Gao; Sheng Wei; Yu-Ping Xie; S R Wayne Chen; Mark E Anderson; Long-Sheng Song Journal: Circ Arrhythm Electrophysiol Date: 2012-06-21
Authors: Chris D Smith; Aixia Wang; Kannan Vembaiyan; Jingqun Zhang; Cuihong Xie; Qiang Zhou; Guogen Wu; S R Wayne Chen; Thomas G Back Journal: J Med Chem Date: 2013-11-05 Impact factor: 7.446
Authors: Jingqun Zhang; Biyi Chen; Xiaowei Zhong; Tao Mi; Ang Guo; Qiang Zhou; Zhen Tan; Guogen Wu; Alexander W Chen; Michael Fill; Long-Sheng Song; S R Wayne Chen Journal: Biochem J Date: 2014-07-01 Impact factor: 3.857
Authors: Randall Loaiza; Nancy A Benkusky; Patricia P Powers; Timothy Hacker; Sami Noujaim; Michael J Ackerman; José Jalife; Héctor H Valdivia Journal: Circ Res Date: 2012-11-14 Impact factor: 17.367