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

Diminished inhibition and facilitated activation of RyR2‐mediated Ca2+ release is a common defect... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Febs Journal Wiley

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

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References (80)

Publisher
Wiley
Copyright
Copyright © 2019 Federation of European Biochemical Societies
ISSN
1742-464X
eISSN
1742-4658
DOI
10.1111/febs.14969
Publisher site
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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.

Journal

The Febs Journal – Wiley

Published: Nov 1, 2019

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