title: Sustained beta1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway.
abstract: A tenet of beta1-adrenergic receptor (beta1AR) 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 beta1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term beta1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) beta1AR 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, beta1AR 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 beta1AR signaling in chronic heart failure.
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Wang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation; D011224:Prazosin / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D000316:Adrenergic alpha-Agonists; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine; D011224:Prazosin; D018342:Receptors, Adrenergic, beta-1; D011993:Recombinant Fusion Proteins; D000099211:Phospholamban