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

35 Citations (Scopus)

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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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Adrenergic Agents
Phosphorylation
Isoproterenol
Hypertrophy
Cardiomyopathies
Knockout Mice
Adrenergic Receptors
Muscle Cells
Catecholamines
Fibrosis

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation. / Grimm, Michael; Ling, Haiyun; Willeford, Andrew; Pereira, Laetitia; Gray, Charles B B; Erickson, Jeffrey R.; Sarma, Satyam; Respress, Jonathan L.; Wehrens, Xander H T; Bers, Donald M; Brown, Joan Heller.

In: Journal of Molecular and Cellular Cardiology, Vol. 85, 04.07.2015, p. 282-291.

Research output: Contribution to journalArticle

Grimm, Michael ; Ling, Haiyun ; Willeford, Andrew ; Pereira, Laetitia ; Gray, Charles B B ; Erickson, Jeffrey R. ; Sarma, Satyam ; Respress, Jonathan L. ; Wehrens, Xander H T ; Bers, Donald M ; Brown, Joan Heller. / CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 85. pp. 282-291.
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T1 - CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation

AU - Grimm, Michael

AU - Ling, Haiyun

AU - Willeford, Andrew

AU - Pereira, Laetitia

AU - Gray, Charles B B

AU - Erickson, Jeffrey R.

AU - Sarma, Satyam

AU - Respress, Jonathan L.

AU - Wehrens, Xander H T

AU - Bers, Donald M

AU - Brown, Joan Heller

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AB - 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.

KW - Beta-adrenergic

KW - CaMKII

KW - Fibrosis

KW - Hypertrophy

KW - Phosphorylation

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