Role of cardiac ryanodine receptor calmodulin-binding domains in mediating the action of arrhythmogenic calmodulin N-domain mutation N54I

Mads T Søndergaard, Yingjie Liu, Wenting Guo, Jinhong Wei, Ruiwu Wang, Malene Brohus, Michael T Overgaard, S R Wayne Chen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

13 Citationer (Scopus)
93 Downloads (Pure)

Abstract

The Ca2+ -sensing protein calmodulin (CaM) inhibits cardiac ryanodine receptor (RyR2)-mediated Ca2+ release. CaM mutations associated with arrhythmias and sudden cardiac death have been shown to diminish CaM-dependent inhibition of RyR2, but the underlying mechanisms are not well understood. Nearly all arrhythmogenic CaM mutations identified are located in the C-domain of CaM and exert marked effects on Ca2+ binding to CaM and on the CaM C-domain interaction with the CaM-binding domain 2 (CaMBD2) in RyR2. Interestingly, the arrhythmogenic N-domain mutation CaM-N54I has little or no effect on Ca2+ binding to CaM or the CaM C-domain-RyR2 CaMBD2 interaction, unlike all CaM C-domain mutations. This suggests that CaM-N54I may diminish CaM-dependent RyR2 inhibition by affecting CaM N-domain interactions with RyR2 CaMBDs other than CaMBD2. To explore this possibility, we assessed the effects of deleting each of the four known CaMBDs in RyR2 (CaMBD1a, -1b, -2, or -3) on the CaM-dependent inhibition of RyR2-mediated Ca2+ release in HEK293 cells. We found that removing CaMBD1a, CaMBD1b, or CaMBD3 did not alter the effects of CaM-N54I or CaM-WT on RyR2 inhibition. On the other hand, deleting RyR2-CaMBD2 abolished the effects of both CaM-N54I and CaM-WT. Our results support that CaM-N54I causes aberrant RyR2 regulation via an uncharacterized CaMBD or less likely CaMBD2, and that RyR2 CaMBD2 is required for the actions of both N- and C-domain CaM mutations. Moreover, our results show that CaMBD1a is central to RyR2 regulation, but CaMBD1a, CaMBD1b, and CaMBD3 are not required for CaM-dependent inhibition of RyR2 in HEK293 cells.

OriginalsprogEngelsk
TidsskriftThe FEBS Journal
Vol/bind287
Udgave nummer11
Sider (fra-til)2256-2280
Antal sider25
ISSN1742-464X
DOI
StatusUdgivet - jun. 2020

Fingeraftryk

Dyk ned i forskningsemnerne om 'Role of cardiac ryanodine receptor calmodulin-binding domains in mediating the action of arrhythmogenic calmodulin N-domain mutation N54I'. Sammen danner de et unikt fingeraftryk.

Citationsformater