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Molecular Pharmacology

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Research ArticleArticle

Stimulation of the Extracellular Signal-Regulated Kinase 1/2 Pathway by Human Beta-3 Adrenergic Receptor: New Pharmacological Profile and Mechanism of Activation

C. C. Gerhardt, J. Gros, A. D. Strosberg and T. Issad
Molecular Pharmacology February 1999, 55 (2) 255-262; DOI: https://doi.org/10.1124/mol.55.2.255
C. C. Gerhardt
Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique and Université Paris VII, Laboratoire d’Immuno-Pharmacologie Moléculaire, Paris, France
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J. Gros
Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique and Université Paris VII, Laboratoire d’Immuno-Pharmacologie Moléculaire, Paris, France
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A. D. Strosberg
Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique and Université Paris VII, Laboratoire d’Immuno-Pharmacologie Moléculaire, Paris, France
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T. Issad
Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique and Université Paris VII, Laboratoire d’Immuno-Pharmacologie Moléculaire, Paris, France
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Abstract

We present evidence that stimulation of the human beta-3 adrenergic receptor (AR), expressed in Chinese hamster ovary/K1 cells, specifically activates the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2, but not JNK or p38. The extent and kinetics of the ERK stimulation by the beta-3 AR are identical with those of the endogenic insulin receptor. However, insulin augments cellular proliferation, whereas beta-3 AR agonists inhibit proliferation due to the production of cyclic AMP. The pharmacological profile of the ERK activation by the beta-3 AR differs significantly from its activation of adenylyl cyclase. The order of potency and intrinsic activities of both natural ligands, norepinephrine and epinephrine, is inversed between both signaling pathways. In addition, BRL 37344 and propranolol, ligands that act as agonists in the stimulation of cyclase, act as antagonists for ERK activation. The activation of ERK1/2 is sensitive to pertussis toxin, suggesting that the beta-3 AR, in addition to its interaction with Gs, can couple to Gi/o. Furthermore, the activation of ERK by the beta-3 AR is sensitive to PD98059, wortmannin, and LY294002, indicating a crucial role for mitogen-activated protein kinase kinase and phosphatidylinositol-3 kinase (PI3K), respectively. Abeta-3 AR-mediated stimulation of PI3K is confirmed by the observation that the selective agonist CGP 12177A specifically activates protein kinase B. As was observed for the activation of ERK, the activation of protein kinase B is inhibited by preincubation with pertussis toxin and PI3K inhibitors, suggesting that both are a consequence of a Gi/o-mediated activation of PI3K.

Footnotes

    • Received July 28, 1998.
    • Accepted October 15, 1998.
  • Send reprint requests to: Dr. T. Issad, Institut Cochin de Génétique Moléculaire, Centre National de la Recherche Scientifique, Unité Propre de Recherche 415, Laboratoire d’Immuno-Pharmacologie Moléculaire, 22, rue Méchain, 75014 Paris, France. E-mail:Issad{at}cochin.inserm.fr

  • This work was supported by the Centre National de la Recherche Scientifique, the Institut National de Santé et de Recherche Médicale, and the Fondation pour la Recherche Médicale.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (2)
Molecular Pharmacology
Vol. 55, Issue 2
1 Feb 1999
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Research ArticleArticle

Stimulation of the Extracellular Signal-Regulated Kinase 1/2 Pathway by Human Beta-3 Adrenergic Receptor: New Pharmacological Profile and Mechanism of Activation

C. C. Gerhardt, J. Gros, A. D. Strosberg and T. Issad
Molecular Pharmacology February 1, 1999, 55 (2) 255-262; DOI: https://doi.org/10.1124/mol.55.2.255

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Research ArticleArticle

Stimulation of the Extracellular Signal-Regulated Kinase 1/2 Pathway by Human Beta-3 Adrenergic Receptor: New Pharmacological Profile and Mechanism of Activation

C. C. Gerhardt, J. Gros, A. D. Strosberg and T. Issad
Molecular Pharmacology February 1, 1999, 55 (2) 255-262; DOI: https://doi.org/10.1124/mol.55.2.255
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