Diminished inhibition and facilitated activation of RyR2-mediated Ca2+ release is a common defect of arrhythmogenic calmodulin mutations.

Abstract

A number of calmodulin (CaM) mutations cause severe cardiac arrhythmias, but their arrhythmogenic mechanisms are unclear. While some of the arrhythmogenic CaM mutations have been shown to impair CaM-dependent inhibition of intracellular Ca2+ release through the ryanodine receptor type 2 (RyR2), the impact of a majority of these mutations on RyR2 function is unknown. Here, we investigated the effect of 14 arrhythmogenic CaM mutations on the CaM-dependent RyR2 inhibition. We found that all the arrhythmogenic CaM mutations tested diminished CaM-dependent inhibition of RyR2-mediated Ca2+ release and increased store-overload induced Ca2+ release (SOICR) in HEK293 cells. Moreover, all the arrhythmogenic CaM mutations tested either failed to inhibit or even promoted RyR2-mediated Ca2+ release in permeabilized HEK293 cells with elevated cytosolic Ca2+ , which was markedly different from the inhibitory action of CaM wild-type. The CaM mutations also altered the Ca2+ -dependency of CaM binding to the RyR2 CaM-binding domain. These results demonstrate that diminished inhibition, and even facilitated activation, of RyR2-mediated Ca2+ release is a common defect of arrhythmogenic CaM mutations.

• Authors: Mads T Søndergaard, Yingjie Liu, Malene Brohus, Wenting Guo, Alma Nani, Catherine Carvajal, Michael Fill, Michael T Overgaard, S R Wayne Chen
• Journal: The FEBS journal (FEBS J) Vol. 286 Issue 22 Pg. 4554-4578 (11 2019) ISSN: 1742-4658 [Electronic] England
• PMID: 31230402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Federation of European Biochemical Societies.

Chemical References

• CACNA1C protein, human
• Calcium Channels, L-Type
• Calmodulin
• Ryanodine Receptor Calcium Release Channel
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Arrhythmias, Cardiac (genetics)
• Binding Sites
• Calcium (metabolism)
• Calcium Channels, L-Type (metabolism)
• Calcium Signaling
• Calmodulin (chemistry, genetics, metabolism)
• HEK293 Cells
• Humans
• Mutation
• Protein Binding
• Ryanodine Receptor Calcium Release Channel (chemistry, metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)