Impact of arrhythmogenic calmodulin variants on small conductance Ca2+‐activated K+ (SK3) channels

Abstract Calmodulin (CaM) is a ubiquitous Ca2+‐sensing protein regulating many important cellular processes. Several CaM‐associated variants have been identified in a small group of patients with cardiac arrhythmias. The mechanism remains largely unknown, even though a number of ion channels, including the ryanodine receptors and the L‐type calcium channels have been shown to be functionally affected by the presence of mutant CaM. CaM is constitutively bound to the SK channel, which underlies the calcium‐gated ISK contributing to cardiac repolarization. The CaM binding to SK channels is essential for gating, correct assembly, and membrane expression. To elucidate the effect of nine different arrhythmogenic CaM variants on SK3 channel function, HEK293 cells stably expressing SK3 were transiently co‐transfected with CaMWT or variant and whole‐cell patch‐clamp recordings were performed with a calculated free Ca2+ concentration of 400 nmol/L. MDCK cells were transiently transfected with SK3 and/or CaMWT or variant to address SK3 and CaM localization by immunocytochemistry. The LQTS‐associated variants CaMD96V, CaMD130G, and CaMF142L reduced ISK,Ca compared with CaMWT (P