Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.

ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress-induced arrhythmogenic disease often caused by point variants in the cardiac ryanodine receptor (RyR2) that enhance diastolic sarcoplasmic reticulum (SR) Ca²⁺ leak. These RyR2 variants cluster in three hot-spots (N-terminal, central and C-terminal domains). We previously demonstrated a pathologic diastolic RyR2 conformation in heart failure, oxidative stress and CaMKII phosphorylation exhibiting a trilogy of effects: (1) reduced calmodulin (CaM)-RyR2 affinity, (2) enhanced unzipping peptide (DPc10) binding and (3) elevated diastolic SR Ca²⁺ leak that are dantrolene-sensitive. Here we test whether this pathological trilogy occurs in CPVT knock-in (KI) mice bearing N-terminal (R176Q/+),

SUBMITTER: Uchinoumi H 

PROVIDER: S-EPMC12787628 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature