RYR2 and chronic obstructive pulmonary disease: The vast majority of the RyR2-linked CPVT mutations studied to date have been found to endow RyR2 channels with a gain of function, that is, the mutations generate hyper-active or hyper-reactive RyR2 channels, and this finding restricts the cellular basis of the cardiac arrhythmias to a well-defined cascade of events, succinctly described as follows: during sympathetic stimulation, enhanced ICa plus enhanced SR Ca2+ uptake promoted by activation of PKA and likely CaMKII, lead to intracellular Ca2+ overload.