Figure 1.

Arrhyhmogenic mechanisms in ventricular myocytes harboring RyR2 mutations linked to CPVT. Left side, CPVT mutations that render RyR2 channels hypo-active or hypo-responsive to stimuli. Depolarization of T-tubules open L-type Ca²⁺ channels (DHPRs, or Ca_v1.2), which induce the opening of RyR2 channels in the SR. Ca²⁺ release from the SR then contributes to inactivate the L-type Ca²⁺ channel current (I_Ca). If Ca²⁺ release is reduced, then there is altered inactivation of I_Ca, prolongation of the action potential, and generation of early afterdepolarizations (EADs). Right side, The vast majority of CPVT mutations endow RyR2 channels with a gain-of-function. Stimulation of β₁-adrenergic receptors by epinephrine activates PKA, which enhances Ca²⁺ entry and accelerates SR Ca²⁺ reuptake by phosphorylating L-type Ca²⁺ channels and phospholamban, respectively. The overall effect of sympathetic stimulation is an intracellular Ca²⁺ overload that increases the strength of contractions. In the process, when SR Ca²⁺ content is elevated, RyR2 channels hyper-sensitized by the CPVT mutations release Ca²⁺ spontaneously, usually in diastole, generating a depolarizing current (delayed afterdepolarization or DAD) as the released Ca²⁺ is extruded by the electrogenic Na⁺/Ca²⁺ exchanger. If Ca²⁺ released is of sufficient mass, it may generate a full action potential, which is the basis for triggered activity. See text for more details.