Abstract

Normal heart contraction requires synchronized calcium ion (Ca 2+ ) release from the sarcoplasmic reticulum (SR), traditionally attributed to ryanodine receptor 2 (RyR2). Here, we identify vacuole membrane protein 1 (VMP1) as a previously unrecognized SR Ca 2+ release channel essential for postnatal cardiac function. VMP1 expression is up-regulated in cardiomyocytes after birth, and its genetic deletion causes severe arrhythmias, dilated cardiomyopathy, and sudden cardiac death. Mechanistically, VMP1 loss results in increased SR Ca 2+ content and aberrant cardiac action potentials. Single-channel electrophysiology reveals that VMP1 forms a Ca 2+ -regulated Ca 2+ channel, which senses luminal Ca 2+ via aspartic acid 272. Notably, VMP1 expression is elevated in human heart failure, suggesting a pathophysiological role. These findings establish VMP1 as a critical component of the cardiac Ca 2+ release machinery and uncover its involvement in heart failure.