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Research ArticleArticle

Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the β1-Adrenergic Receptor

Ségolène Galandrin, Geneviève Oligny-Longpré, Hélène Bonin, Koji Ogawa, Céline Galés and Michel Bouvier
Molecular Pharmacology July 2008, 74 (1) 162-172; DOI: https://doi.org/10.1124/mol.107.043893
Ségolène Galandrin
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Geneviève Oligny-Longpré
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Hélène Bonin
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Koji Ogawa
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Céline Galés
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Michel Bouvier
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Abstract

In recent years, several studies have demonstrated that different ligands can have distinct efficacy profiles toward various signaling pathways through a unique receptor. For example, β1-adrenergic compounds that are inverse agonists toward the adenylyl cyclase (AC) can display agonist activity for the mitogen-activated protein kinase (MAPK) pathway. Such a phenomenon, often termed functional selectivity, has now been clearly established for many G protein-coupled receptors when considering distinct signaling output. However, the possibility that ligands could selectively engage distinct effectors to activate a single signaling output by promoting specific receptor conformations has not been extensively examined. Here, we took advantage of the fact that isoproterenol, bucindolol and propranolol (full, partial, and inverse agonists for the AC pathway, respectively) all activate MAPK through the β1-adrenergic receptor (β1AR) to probe such conformational-biased signaling. Although the three compounds stimulated MAPK in a src-dependent manner, isoproterenol acted through both Gαiβγ- and G protein-independent pathways, whereas bucindolol and propranolol promoted MAPK activation through the G protein-independent pathway only. The existence of such distinct signaling cascades linking β1AR to MAPK activation was correlated with ligand-specific conformational rearrangements of receptor/G protein complexes measured by bioluminescence resonance energy transfer. Taken together, our data indicate that discrete local conformational changes can selectively promote the recruitment of distinct proximal signaling partners that can engage distinct signaling outputs and/or converge on the same signaling output.

Footnotes

  • This work was supported by grants from the Canadian Institute for Health Research (CIHR) and the Québec Heart and Stroke Foundation. G.O.-L. was supported by a studentship from the CIHR; K.O. was an invited researcher from Tanabe Seiyaku Co. Ltd.; and M.B. holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology.

  • C.G. and M.B. contributed equally to this work.

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; βAR, β-adrenergic receptor; AC, adenylyl cyclase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; BRET, bioluminescence resonance energy transfer; AVP, arginine 8 vasopressin; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; PD98059, 2′-amino-3′-methoxyflavone; EGF, epidermal growth factor; CTX, cholera toxin B; PTX, pertussis toxin; PKA, protein kinase A; HRP, horseradish peroxidase; GFP, green fluorescent protein; GFP10, blue-shifted mutant of green fluorescent protein; βARK, β-adrenergic receptor kinase; HEK, human embryonic kidney; δOR, δ opioid receptor; V2R, vasopressin type 2 receptor; PTH, parathyroid hormone; siRNA, small interfering RNA; PBS, phosphate-buffered saline; Rluc, Renilla reniformis luciferase; TBS-T, Tris-buffered saline/Tween 20; p-, phospho; MEK, mitogen-activated protein kinase kinase.

  • ↵1 Current affiliation: Institut National de la Santé et de la Recherche Médicale U858-I2MR-Equipe 8, Toulouse, France.

    • Received December 6, 2007.
    • Accepted April 2, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (1)
Molecular Pharmacology
Vol. 74, Issue 1
1 Jul 2008
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Research ArticleArticle

Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the β1-Adrenergic Receptor

Ségolène Galandrin, Geneviève Oligny-Longpré, Hélène Bonin, Koji Ogawa, Céline Galés and Michel Bouvier
Molecular Pharmacology July 1, 2008, 74 (1) 162-172; DOI: https://doi.org/10.1124/mol.107.043893

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Research ArticleArticle

Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased Mitogen-Activated Protein Kinase Signaling through the β1-Adrenergic Receptor

Ségolène Galandrin, Geneviève Oligny-Longpré, Hélène Bonin, Koji Ogawa, Céline Galés and Michel Bouvier
Molecular Pharmacology July 1, 2008, 74 (1) 162-172; DOI: https://doi.org/10.1124/mol.107.043893
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