Inhibition of spontaneous β2-adrenergic activation rescues β1- adrenergic contractile response in cardiomyocytes overexpressing β2- adrenoceptor

Sheng Jun Zhang, Heping Cheng, Ying Ying Zhou, Ding Ji Wang, Weizhong Zhu, Bruce Ziman, Harold Spurgoen, Robert J. Lefkowitz, Edward G. Lakatta, Walter J. Koch, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac-specific overexpression of the human β2-adrenergic receptor (AR) in transgenic mice (TG4) enhances basal cardiac function due to ligand- independent spontaneous β2-AR activation. However, agonist-mediated stimulation of either β1-AR or β2-AR fails to further enhance contractility in TG4 ventricular myocytes. Although the lack of β2-AR response 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 β1-AR stimulation by norepinephrine and an α1-adrenergic antagonist prazosin is not restored by pertussis toxin treatment despite a G(i) protein elevation of 1.7-fold in TG4 hearts. Since β-adrenergic receptor kinase, βARK1, activity remains unaltered, the unresponsiveness of β1-AR is not caused by βARK1-mediated receptor desensitization. In contrast, pre-incubation of cells with anti-adrenergic reagents such as muscarinic receptor agonist, carbachol (10-5 M), or a β2-AR inverse agonist, ICI 118,551 (5 x 10-7 M), to abolish spontaneous β2-AR signaling, both reduce the base-line cAMP and contractility and, surprisingly, restore the β1-AR contractile response. The 'rescued' contractile response is completely reversed by a β1-AR antagonist, CGP 20712A. Furthermore, these results from the transgenic animals are corroborated by in vitro acute gene manipulation in cultured wild type adult mouse ventricular myocytes. Adenovirus-directed overexpression of the human β2-AR results in elevated baseline cAMP and contraction associated with a marked attenuation of β1-AR response; carbachol pretreatment fully revives the diminished β1-AR contractile response. Thus, we conclude that constitutive β2-AR activation induces a heterologous desensitization of β1-ARs independent of βARK1 and G(i) proteins; suppression of the constitutive β2-AR signaling by either a β2-AR inverse agonist or stimulation of the muscarinic receptor rescues the β1-ARs from desensitization, permitting agonist-induced contractile response.

Original languageEnglish (US)
Pages (from-to)21773-21779
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number28
DOIs
StatePublished - Jul 14 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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