Defective conformational regulation of the ryanodine receptor as a key pathogenic mechanism of catecholaminergic polymorphic ventricular tachycardia

Creators Uchinoumi Hitoshi

Creators Yano Masafumi

Creators Matsuzaki Masunori

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life-threatening arrhythmias elicited by stress and emotion. CPVT is known to be caused by a mutation-linked channel disorder in the cardiac ryanodine receptor (RyR2). However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved. The unique distribution of these mutation sites has led to the concept that interaction among the putative regulatory domains within the RyR has a key role in regulating channel opening. Here, we report that introduction of R2474S CPVT mutation into the central domain of mouse RyR2 interfered with a normal tight interaction between the central domain (aa 2000–2500) and the N-terminal domain (aa 1-600), which reduced the threshold of luminal [Ca^<2+>] for channel activation, sensitized to the protein kinase A-dependent phosphorylation, and in turn led to CPVT.