Show simple item record

dc.contributor.author Xiao, RP
dc.contributor.author Avdonin, P
dc.contributor.author Zhou, YY
dc.contributor.author Cheng, H
dc.contributor.author Akhter, SA
dc.contributor.author Eschenhagen, T
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.contributor.author Lakatta, EG
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T21:24:29Z
dc.date.issued 1999-01-08
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/9915773
dc.identifier.citation Circ Res, 1999, 84 (1), pp. 43 - 52
dc.identifier.issn 0009-7330
dc.identifier.uri http://hdl.handle.net/10161/5912
dc.description.abstract -Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particularly those of beta2-adrenergic receptor (beta2AR) stimulation, have not been characterized. In the present study, we investigated effects of beta2AR stimulation on contraction, [Ca2+]i transient, and L-type Ca2+ currents (ICa) in single ventricular myocytes isolated from transgenic mice overexpressing human beta2AR (TG4 mice) and wild-type (WT) littermates. Baseline contractility of TG4 heart cells was increased by 3-fold relative to WT controls as a result of the presence of spontaneous beta2AR activation. In contrast, beta2AR stimulation by zinterol or isoproterenol plus a selective beta1-adrenergic receptor (beta1AR) antagonist CGP 20712A failed to enhance the contractility in TG4 myocytes, and more surprisingly, beta2AR stimulation was also ineffective in increasing contractility in WT myocytes. Pertussis toxin (PTX) treatment fully rescued the ICa, [Ca2+]i, and contractile responses to beta2AR agonists in both WT and TG4 cells. The PTX-rescued murine cardiac beta2AR response is mediated by cAMP-dependent mechanisms, because it was totally blocked by the inhibitory cAMP analog Rp-cAMPS. These results suggest that PTX-sensitive G proteins are responsible for the unresponsiveness of mouse heart to agonist-induced beta2AR stimulation. This was further corroborated by an increased incorporation of the photoreactive GTP analog [gamma-32P]GTP azidoanilide into alpha subunits of Gi2 and Gi3 after beta2AR stimulation by zinterol or isoproterenol plus the beta1AR blocker CGP 20712A. This effect to activate Gi proteins was abolished by a selective beta2AR blocker ICI 118,551 or by PTX treatment. Thus, we conclude that (1) beta2ARs in murine cardiac myocytes couple to concurrent Gs and Gi signaling, resulting in null inotropic response, unless the Gi signaling is inhibited; (2) as a special case, the lack of cardiac contractile response to beta2AR agonists in TG4 mice is not due to a saturation of cell contractility or of the cAMP signaling cascade but rather to an activation of beta2AR-coupled Gi proteins; and (3) spontaneous beta2AR activation may differ from agonist-stimulated beta2AR signaling.
dc.format.extent 43 - 52
dc.language ENG
dc.relation.ispartof Circ Res
dc.subject Adrenergic beta-Agonists
dc.subject Adrenergic beta-Antagonists
dc.subject Animals
dc.subject Calcium
dc.subject Calcium Channels
dc.subject Calcium Channels, L-Type
dc.subject Cells, Cultured
dc.subject Colforsin
dc.subject Cyclic AMP
dc.subject Ethanolamines
dc.subject GTP-Binding Proteins
dc.subject Heart
dc.subject Heart Ventricles
dc.subject Humans
dc.subject Imidazoles
dc.subject Isoproterenol
dc.subject Male
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Myocardial Contraction
dc.subject Myocardium
dc.subject Norepinephrine
dc.subject Pertussis Toxin
dc.subject Propanolamines
dc.subject Receptors, Adrenergic, beta-2
dc.subject Thionucleotides
dc.subject Virulence Factors, Bordetella
dc.title Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.
dc.type Journal Article
duke.description.endpage 52 en_US
duke.description.issue 1 en_US
duke.description.startpage 43 en_US
duke.description.volume 84 en_US
dc.relation.journal Circulation Research en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/9915773
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 84

Files in this item

This item appears in the following Collection(s)

Show simple item record