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- Title
A gain of function ryanodine receptor 2 mutation (R1760W‐RyR2) in catecholaminergic polymorphic ventricular tachycardia.
- Authors
Li, Siyuan; Lv, Tingting; Yang, Jing; Li, Kun; Yang, Ying; Zhang, Ping
- Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with Ca2+ leak predominantly caused by ryanodine receptor 2 (RyR2) mutations. We identified a R1760W‐RyR2 mutation located between the N‐terminal domain and the central domain of RyR2 in a CPVT patient by DNA sequencing. Recombinant mutant RyR2−2801mcherry plasmid generated by the overlap extension polymerase chain reaction and seamless cloning was transfected in HEK293 cells for the cell model. Single‐cell luminal and cytosolic Ca2+ imaging was measured by endoplasmic reticulum (ER) luminal Ca2+‐sensitive protein D1ER and Fura‐2 AM on a confocal laser scanning microscope, respectively. We found that in RyR2 mutant cells, the propensity for store‐overload‐induced Ca2+ release (SOICR) was enhanced representing increased Ca2+ oscillations, reduced activation and termination thresholds of spontaneous Ca2+ release; and the sensitivity to cytosolic Ca2+ activation was increased manifesting reduced steady state ER Ca2+ levels. Our results indicated that R1760W‐RyR2 mutation induced calcium leak, representing a gain of function. Further, antiarrhythmic drugs propafenone and flecainide significantly suppressed SOICR caused by the R1760W‐RyR2 mutation at a concentration of 20 μM, which was lower than the concentration at which carvedilol suppressed SOICR.
- Subjects
VENTRICULAR tachycardia; RYANODINE receptors; ARRHYTHMIA; ACTIVATION energy; POLYMERASE chain reaction; CALCIUM ions
- Publication
Clinical & Experimental Pharmacology & Physiology, 2023, Vol 50, Issue 1, p39
- ISSN
0305-1870
- Publication type
Article
- DOI
10.1111/1440-1681.13722