Send to

Choose Destination
Circ Res. 2011 Jul 22;109(3):281-90. doi: 10.1161/CIRCRESAHA.111.244970. Epub 2011 Jun 9.

A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium.

Author information

Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.



Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during β-adrenergic stimulation.


This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca(2+)).


Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2. RyR2 channels were measured to examine the regulation of the channels by cytosolic versus luminal sarcoplasmic reticulum Ca(2+). A 50-year-old white man with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. cAMP-dependent protein kinase-phosphorylated RyR2-G230C channels exhibited a significantly higher open probability at diastolic Ca(2+) concentrations, associated with a depletion of calstabin2. The luminal Ca(2+) sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like.


The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca(2+) dependence for activation under conditions that simulate exercise, consistent with a "leaky" channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca(2+) activation. Thus, diastolic sarcoplasmic reticulum Ca(2+) leak caused by reduced calstabin2 binding and a leftward shift in the Ca(2+) dependence for activation by diastolic levels of cytosolic Ca(2+) is a common mechanism underlying CPVT.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center