The cardiac ryanodine receptor (RyR2), the major calcium release channel on the 
sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be 
involved in at least two forms of sudden cardiac death (SCD): (1) 
Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial 
polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 
(ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All 
eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the 
three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of 
the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 
mutations have been shown to alter calcium-induced calcium release. Sympathetic 
nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A 
(PKA). PKA phosphorylation of RyR2 activates the channel. In conditions 
associated with high rates of SCD such as heart failure RyR2 is PKA 
hyperphosphorylated resulting in "leaky" channels. SR calcium leak during 
diastole can generate "delayed after depolarizations" that can trigger fatal 
cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic 
forms of catecholaminergic-induced SCD may alter the regulation of the channel 
resulting in increased SR calcium leak during sympathetic stimulation.