Open AccessPhosphorylation of RyR2 Ser‐2814 by CaMKII mediates β1‐adrenergic stress induced Ca 2+ ‐leak from the sarcoplasmic reticulum
Author(s) -
Baier Maria J.,
Noack Jannis,
Seitz Mark Tilmann,
Maier Lars S.,
Neef Stefan
Publication year - 2021
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.13274
Subject(s) - ryanodine receptor 2 , endoplasmic reticulum , ryanodine receptor , chemistry , phosphorylation , medicine , endocrinology , leak , adrenergic , microbiology and biotechnology , receptor , biology , biochemistry , environmental engineering , engineering
Adrenergic stimulation, while being the central mechanism of cardiac positive inotropy, is a universally acknowledged inductor of undesirable sarcoplasmic reticulum (SR) Ca 2+ leak. However, the exact mechanisms for this remained unspecified so far. This study shows that Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII)‐specific phosphorylation of ryanodine receptor type 2 at Ser‐2814 is the pivotal mechanism by which SR Ca 2+ leak develops downstream of β1‐adrenergic stress by increase of the leak/load relationship. Cardiomyocytes with a Ser‐2814 phosphoresistant mutation (S2814A) were protected from isoproterenol‐induced SR Ca 2+ leak and consequently displayed improved postrest potentiation of systolic Ca 2+ release under adrenergic stress compared to littermate wild‐type cells.