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.


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    Title :

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


    Contributors:

    Publication date :

    2020-06-01


    Remarks:

    Søndergaard , M T , Liu , Y , Guo , W , Wei , J , Wang , R , Brohus , M , Overgaard , M T & Chen , S R W 2020 , ' Role of cardiac ryanodine receptor calmodulin-binding domains in mediating the action of arrhythmogenic calmodulin N-domain mutation N54I ' , The FEBS Journal , vol. 287 , no. 11 , pp. 2256-2280 . https://doi.org/10.1111/febs.15147



    Type of media :

    Article (Journal)


    Type of material :

    Electronic Resource


    Language :

    English



    Classification :

    DDC:    629