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

Research output: Contribution to journalArticle

37 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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    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