Mutation-Linked Defective Interdomain Interactions Within Ryanodine Receptor Cause Aberrant Ca ²⁺ Release Leading to Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

The catecholaminergic polymorphic ventricular tachycardia-linked mutation of RyR2, S2246L, causes an abnormally tight local subdomain-subdomain interaction within the central domain involving the mutation site, which induces defective interaction between the N-terminal and central domains. This results in an erroneous activation of Ca²⁺ channel in a diastolic state reflecting on the increased Ca²⁺ spark frequency, which then leads to lethal arrhythmia.