title: CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic β-adrenergic stimulation.
abstract: Chronic activation of Ca(2+)/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) Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Willeford
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Charles B B
authors.initials: CB
authors.lastname: Gray
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Erickson
authors.affiliation: Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Satyam
authors.initials: S
authors.lastname: Sarma
authors.affiliation: Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.affiliation: Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA. Electronic address: jhbrown@ucsd.edu.
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology; D009202:Cardiomyopathies / Q000201:enzymology; D002478:Cells, Cultured; D005355:Fibrosis; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D020257:Ventricular Remodeling; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban; C000592748:ryanodine receptor 2. mouse
keywords: Beta-adrenergic; CaMKII; Fibrosis; Hypertrophy; Phosphorylation