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

Mads T Søndergaard, Yingjie Liu, Malene Brohus, Wenting Guo, Alma Nani, Catherine Carvajal, Michael Fill, Michael T Overgaard, S R Wayne Chen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

17 Citationer (Scopus)
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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 Ca 2+ 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 Ca 2+ release and increased store-overload induced Ca 2+ release (SOICR) in HEK293 cells. Moreover, all the arrhythmogenic CaM mutations tested either failed to inhibit or even promoted RyR2-mediated Ca 2+ release in permeabilized HEK293 cells with elevated cytosolic Ca 2+, which was markedly different from the inhibitory action of CaM wild-type. The CaM mutations also altered the Ca 2+-dependency of CaM binding to the RyR2 CaM-binding domain. These results demonstrate that diminished inhibition, and even facilitated activation, of RyR2–mediated Ca 2+ release is a common defect of arrhythmogenic CaM mutations.

OriginalsprogEngelsk
TidsskriftF E B S Journal
Vol/bind286
Udgave nummer22
Sider (fra-til)4554-4578
Antal sider25
ISSN1742-464X
DOI
StatusUdgivet - nov. 2019

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