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Phosphorylation of RyR2 Ser‐2814 by CaMKII mediates β1‐adrenergic stress induced Ca(2+)‐leak from the sarcoplasmic reticulum

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...

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Detalles Bibliográficos
Autores principales: Baier, Maria J., Noack, Jannis, Seitz, Mark Tilmann, Maier, Lars S., Neef, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487045/
https://www.ncbi.nlm.nih.gov/pubmed/34403217
http://dx.doi.org/10.1002/2211-5463.13274
Descripción
Sumario: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.