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Molecular Pharmacology

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Research ArticleArticle

Spontaneous Activation of β2- but Not β1-Adrenoceptors Expressed in Cardiac Myocytes from β1β2 Double Knockout Mice

Ying-Ying Zhou, Dongmei Yang, Wei-Zhong Zhu, Sheng-Jun Zhang, Ding-Ji Wang, Dan K. Rohrer, Eric Devic, Brian K. Kobilka, Edward G. Lakatta, Heping Cheng and Rui-Ping Xiao
Molecular Pharmacology November 2000, 58 (5) 887-894; DOI: https://doi.org/10.1124/mol.58.5.887
Ying-Ying Zhou
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Dongmei Yang
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Wei-Zhong Zhu
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Sheng-Jun Zhang
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Ding-Ji Wang
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Dan K. Rohrer
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Eric Devic
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Brian K. Kobilka
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Edward G. Lakatta
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Heping Cheng
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Rui-Ping Xiao
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Abstract

Although ligand-free, constitutive β2-adrenergic receptor (AR) signaling has been demonstrated in naive cell lines and in transgenic mice overexpressing cardiac β2-AR, it is unclear whether the dominant cardiac β-AR subtype, β1-AR, shares the ability of spontaneous activation. In the present study, we expressed human β1- or β2-AR via recombinant adenoviral infection in ventricular myocytes isolated from β1β2-AR double knockout mice, creating pure β1-AR and β2-AR systems with variable receptor densities. A contractile response to a nonselective β-AR agonist, isoproterenol, was absent in double knockout mouse myocytes but was fully restored after adenoviral β1-AR or adenoviral β2-AR infection. Increasing the titer of adenoviral vectors (multiplicity of infection 10–1000) led to a dose-dependent expression of β1- or β2-AR with a maximal density of 1207 ± 173 (36-fold over the wild-type control value) and 821 ± 38 fmol/mg protein (69-fold), respectively. Using confocal immunohistochemistry, we directly visualized the cellular distribution of β1-AR and β2-AR and found that both subtypes were distributed on the cell surface membrane and transverse tubules, resulting in a striated pattern. In the absence of ligand, β2-AR expression resulted in graded increases in baseline cAMP and contractility up to 428% and 233% of control, respectively, at the maximal β2-AR density. These effects were specifically reversed by a β2-AR inverse agonist, ICI 118,551 (10−7 M). In contrast, overexpression of β1-AR, even at a greater density, failed to enhance either basal cAMP or contractility; the alleged β1-AR inverse agonist, CGP 20712A (10−6 M), had no significant effect on basal contraction in these cells. Thus, we conclude that acute β2-AR overexpression in cardiac myocytes elicits significant physiological responses due to spontaneous receptor activation; however, this property is β-AR subtype specific because β1-AR does not exhibit agonist-independent spontaneous activation.

Footnotes

    • Received March 24, 2000.
    • Accepted July 18, 2000.
  • Send reprint requests to: Rui-Ping Xiao, M.D., Ph.D., Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. E-mail:xiaor{at}grc.nia.nih.gov

  • ↵1 Present address: Pediatric Cardiology, New York University Medical Center, New York, NY 10016.

  • This work was supported by National Institutes of Health intramural (E.G.L., H.C., R.-P.X.) and extramural grants (B.K.K.), and by a grant from the National Science Foundation for Outstanding Youth of China (H.C.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

Spontaneous Activation of β2- but Not β1-Adrenoceptors Expressed in Cardiac Myocytes from β1β2 Double Knockout Mice

Ying-Ying Zhou, Dongmei Yang, Wei-Zhong Zhu, Sheng-Jun Zhang, Ding-Ji Wang, Dan K. Rohrer, Eric Devic, Brian K. Kobilka, Edward G. Lakatta, Heping Cheng and Rui-Ping Xiao
Molecular Pharmacology November 1, 2000, 58 (5) 887-894; DOI: https://doi.org/10.1124/mol.58.5.887

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Research ArticleArticle

Spontaneous Activation of β2- but Not β1-Adrenoceptors Expressed in Cardiac Myocytes from β1β2 Double Knockout Mice

Ying-Ying Zhou, Dongmei Yang, Wei-Zhong Zhu, Sheng-Jun Zhang, Ding-Ji Wang, Dan K. Rohrer, Eric Devic, Brian K. Kobilka, Edward G. Lakatta, Heping Cheng and Rui-Ping Xiao
Molecular Pharmacology November 1, 2000, 58 (5) 887-894; DOI: https://doi.org/10.1124/mol.58.5.887
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