Based on the domain-switch hypothesis proposed by Ikemoto and his colleagues6, we have shown that defective inter-domain interactions between the N-terminal domain (a.a. 1–600) and the central domain (a.a. 2000–2500) of RyR2 (domain unzipping), causes Ca2+ leakage through RyR2, inducing catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure7–10. The gene discussed is RYR2; the disease is catecholaminergic polymorphic ventricular tachycardia.