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 ventricular arrhythmias in young 
individuals during β-adrenergic stimulation.
OBJECTIVE: 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+)).
METHODS AND RESULTS: 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.
CONCLUSIONS: 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.