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

  • Author(s): Grimm, M
  • Ling, H
  • Willeford, A
  • Pereira, L
  • Gray, CBB
  • Erickson, JR
  • Sarma, S
  • Respress, JL
  • Wehrens, XHT
  • Bers, DM
  • Brown, JH
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530053/
No data is associated with this publication.
Abstract

© 2015 Elsevier Ltd. 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.

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