Inhibition of spontaneous beta(2)-adrenergic activation rescues beta(1)-adrenergic contractile response in cardiomyocytes overexpressing beta(2)-adrenoceptor

Citation
Sj. Zhang et al., Inhibition of spontaneous beta(2)-adrenergic activation rescues beta(1)-adrenergic contractile response in cardiomyocytes overexpressing beta(2)-adrenoceptor, J BIOL CHEM, 275(28), 2000, pp. 21773-21779
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
275
Issue
28
Year of publication
2000
Pages
21773 - 21779
Database
ISI
SICI code
0021-9258(20000714)275:28<21773:IOSBAR>2.0.ZU;2-K
Abstract
Cardiac-specific overexpression of the human beta(2)-adrenergic receptor (A R) in transgenic mice (TG4) enhances basal cardiac function due to ligand-i ndependent spontaneous beta(2)-AR activation. However, agonist-mediated sti mulation of either beta(1)-AR or beta(2)-AR fails to further enhance contra ctility in TG4 ventricular myocytes. Although the lack of beta(2)-AR respon se has been ascribed to an efficient coupling of the receptor to pertussis toxin-sensitive G(i) proteins in addition to G(s), the contractile response to beta(1)-AR stimulation by norepinephrine and an alpha(1)-adrenergic ant agonist prazosin is not restored by pertussis toxin treatment despite a G(i ) protein elevation of 1.7-fold in TG4 hearts. Since beta-adrenergic recept or kinase, beta ARK1, activity remains unaltered, the unresponsiveness of b eta(1)-AR is not caused by beta ARK1-mediated receptor desensitization. In contrast, pre-incubation of cells with anti-adrenergic reagents such as mus carinic receptor agonist, carbachol (10(-5) M), or a beta(2)-AR inverse ago nist, ICI 118,551 (5 x 10(-7) M), to abolish spontaneous beta(2)-AR signali ng, both reduce the base-line cAMP and contractility and, surprisingly, res tore the beta(1)-AR contractile response. The "rescued" contractile respons e is completely reversed by a beta(1)-AR antagonist, CGP 20712A. Furthermor e, these results from the transgenic animals are corroborated by in vitro a cute gene manipulation in cultured wild type adult mouse ventricular myocyt es. Adenovirus-directed overexpression of the human beta(2)-AR results in e levated baseline cAMP and contraction associated with a marked attenuation of beta(1)-AR response; carbachol pretreatment fully revives the diminished beta(1)-AR contractile response. Thus, we conclude that constitutive beta( 2)-AR activation induces a heterologous desensitization of beta(1)-ARs inde pendent of beta ARK1 and G(i) proteins; suppression of the constitutive bet a(2)-AR signaling by either a beta(2)-AR inverse agonist or stimulation of the muscarinic receptor rescues the beta(1)-ARs from desensitization, permi tting agonist-induced contractile response.