A CACNA1C variant associated with cardiac arrhythmias provides mechanistic insights in the calmodulation of L-type Ca²⁺ channels.

ABSTRACT: We recently reported the identification of a de novo single nucleotide variant in exon 9 of CACNA1C associated with prolonged repolarization interval. Recombinant expression of the glycine to arginine variant at position 419 produced a gain in the function of the L-type Ca_V1.2 channel with increased peak current density and activation gating but without significant decrease in the inactivation kinetics. We herein reveal that these properties are replicated by overexpressing calmodulin (CaM) with Ca_V1.2 WT and are reversed by exposure to the CaM antagonist W-13. Phosphomimetic (T79D or S81D), but not phosphoresistant (T79A or S81A), CaM surrogates reproduced the impact of CaM WT on the function of Ca_V1.2 WT. The increased channel activity of Ca_V1.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC9691931 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature