The Arrhythmogenic Calmodulin p.Phe142Leu Mutation Impairs C-domain Ca2+ Binding but Not Calmodulin-dependent Inhibition of the Cardiac Ryanodine Receptor.

ABSTRACT: A number of point mutations in the intracellular Ca²⁺-sensing protein calmodulin (CaM) are arrhythmogenic, yet their underlying mechanisms are not clear. These mutations generally decrease Ca²⁺ binding to CaM and impair inhibition of CaM-regulated Ca²⁺ channels like the cardiac Ca²⁺ release channel (ryanodine receptor, RyR2), and it appears that attenuated CaM Ca²⁺ binding correlates with impaired CaM-dependent RyR2 inhibition. Here, we investigated the RyR2 inhibitory action of the CaM p.Phe142Leu mutation (F142L; numbered including the start-Met), which markedly reduces CaM Ca²⁺ binding. Surprisingly, CaM-F142L had little to no aberrant effect on RyR2-mediated store overload-induced Ca²⁺ release in HEK293 cells

SUBMITTER: Sondergaard MT 

PROVIDER: S-EPMC5270481 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature