Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway

Wang Wang, Weizhong Zhu, Shiqiang Wang, Dongmei Yang, Michael T. Crow, Rui Ping Xiao, Heping Cheng

Research output: Contribution to journalArticle

Abstract

A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.

Original languageEnglish (US)
Pages (from-to)798-806
Number of pages9
JournalCirculation Research
Volume95
Issue number8
DOIs
StatePublished - Oct 15 2004

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Adrenergic Agents
Cyclic AMP-Dependent Protein Kinases
Adrenergic Receptors
Excitation Contraction Coupling
Protein Kinase Inhibitors
Adenylyl Cyclases
Cardiac Myocytes
Norepinephrine
Heart Failure
Phosphorylation
Apoptosis

Keywords

  • β-adrenergic receptor
  • Ca/calmodulin- dependent
  • cAMP-dependent protein kinase
  • Cardiac contractility
  • Phospholamban
  • Protein kinase II

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. / Wang, Wang; Zhu, Weizhong; Wang, Shiqiang; Yang, Dongmei; Crow, Michael T.; Xiao, Rui Ping; Cheng, Heping.

In: Circulation Research, Vol. 95, No. 8, 15.10.2004, p. 798-806.

Research output: Contribution to journalArticle

Wang, Wang ; Zhu, Weizhong ; Wang, Shiqiang ; Yang, Dongmei ; Crow, Michael T. ; Xiao, Rui Ping ; Cheng, Heping. / Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. In: Circulation Research. 2004 ; Vol. 95, No. 8. pp. 798-806.
@article{54796039e19f4a43acddaa0e81904a9a,
title = "Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway",
abstract = "A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.",
keywords = "β-adrenergic receptor, Ca/calmodulin- dependent, cAMP-dependent protein kinase, Cardiac contractility, Phospholamban, Protein kinase II",
author = "Wang Wang and Weizhong Zhu and Shiqiang Wang and Dongmei Yang and Crow, {Michael T.} and Xiao, {Rui Ping} and Heping Cheng",
year = "2004",
month = "10",
day = "15",
doi = "10.1161/01.RES.0000145361.50017.aa",
language = "English (US)",
volume = "95",
pages = "798--806",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway

AU - Wang, Wang

AU - Zhu, Weizhong

AU - Wang, Shiqiang

AU - Yang, Dongmei

AU - Crow, Michael T.

AU - Xiao, Rui Ping

AU - Cheng, Heping

PY - 2004/10/15

Y1 - 2004/10/15

N2 - A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.

AB - A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.

KW - β-adrenergic receptor

KW - Ca/calmodulin- dependent

KW - cAMP-dependent protein kinase

KW - Cardiac contractility

KW - Phospholamban

KW - Protein kinase II

UR - http://www.scopus.com/inward/record.url?scp=6344258936&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=6344258936&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000145361.50017.aa

DO - 10.1161/01.RES.0000145361.50017.aa

M3 - Article

C2 - 15375008

AN - SCOPUS:6344258936

VL - 95

SP - 798

EP - 806

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 8

ER -