Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function

Lamin A/C Ser 22 phosphorylation can modulate Nav1.5 function and contributes to the mechanism by which R545H-LMNA alters Nav1.5 function in cardiac conduction disease. Abolishing phosphorylation with S22A-LMNA reduces channel function, but decreasing phosphorylation with the small molecule LBL1 does not, suggesting a threshold of Ser 22 phosphorylation required for Nav1.5 modulation. Mimicking phosphorylation with S22D-R545H-LMNA abolished the effects of mutant R545H-LMNA on voltage-dependency but not peakINa. AbstractVariants in theLMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peakINa in HEK-293 cells expressing Nav1.5. Decreased peakINa in the cardiac conduction system could account for patients ’ atrioventricular block. We found that serine 22 (Ser 22) phosphorylation of Lamin A/C was decreased in the p.R545H variant and hypothesized that lamin phosphorylation modulated Nav1.5 activity. To test this hypothesis, we assessed Nav1.5 function in HEK-293 cells co-transfected withLMNA variants or treated with the small molecule LBL1 (lamin-binding ligand 1). LBL1 decreased Ser 22 phosphorylation by 65% but did not affect Nav1.5 function. To test the complete loss of phosphorylation, we generated a version ofLMNA with serine 22 converted to alanine 22 (S22A-LMNA); and a version of mutantR545H-LMNA that mimics...

Source: Physiological Reports - November 23, 2021 Category: Physiology Authors: Michael A. Olaopa, Tomohiko Ai, Bo Chao, Xiangshu Xiao, Matteo Vatta, Beth A. Habecker Tags: ORIGINAL ARTICLE Source Type: research