CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation

Michael Grimm, Haiyun Ling, Andrew Willeford, Laetitia Pereira, Charles B.B. Gray, Jeffrey R. Erickson, Satyam Sarma, Jonathan L. Respress, Xander H.T. Wehrens, Donald M. Bers, Joan Heller Brown

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35 Scopus citations

Abstract

Chronic activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the deleterious effects of β-adrenergic receptor (β-AR) signaling on the heart, in part, by enhancing RyR2-mediated sarcoplasmic reticulum (SR) Ca2+ leak. We used CaMKIIδ knockout (CaMKIIδ-KO) mice and knock-in mice with an inactivated CaMKII site S2814 on the ryanodine receptor type 2 (S2814A) to investigate the involvement of these processes in β-AR signaling and cardiac remodeling. Langendorff-perfused hearts from CaMKIIδ-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKIIδ-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKIIδ-KO mice had reduced SR Ca2+ leak in response to isoproterenol (ISO). Chronic catecholamine stress with ISO induced comparable increases in relative heart weight and other measures of hypertrophy from day 9 through week 4 in WT and CaMKIIδ-KO mice, but the development of cardiac fibrosis was prevented in CaMKIIδ-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKIIδ-KO or S2814A mice, implicating CaMKIIδ-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged β-AR stimulation.

Original languageEnglish (US)
Pages (from-to)282-291
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume85
DOIs
StatePublished - Jul 4 2015

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Keywords

  • Beta-adrenergic
  • CaMKII
  • Fibrosis
  • Hypertrophy
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Grimm, M., Ling, H., Willeford, A., Pereira, L., Gray, C. B. B., Erickson, J. R., Sarma, S., Respress, J. L., Wehrens, X. H. T., Bers, D. M., & Brown, J. H. (2015). CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation. Journal of Molecular and Cellular Cardiology, 85, 282-291. https://doi.org/10.1016/j.yjmcc.2015.06.007