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Research ArticleArticle

Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity

Ivana Domazet, Brian J. Holleran, Alexandra Richard, Camille Vandenberghe, Pierre Lavigne, Emanuel Escher, Richard Leduc and Gaétan Guillemette
Molecular Pharmacology June 2015, 87 (6) 982-995; DOI: https://doi.org/10.1124/mol.114.097337
Ivana Domazet
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Brian J. Holleran
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Alexandra Richard
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Camille Vandenberghe
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Pierre Lavigne
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Emanuel Escher
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Richard Leduc
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Gaétan Guillemette
Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Abstract

The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein–coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal–regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)–dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι.

Footnotes

    • Received December 8, 2014.
    • Accepted March 24, 2015.
  • This work was supported by a grant from the Canadian Institutes of Health Research [Grant MOP-136770].

  • This work is part of the Ph.D. thesis of I. Domazet.

  • dx.doi.org/10.1124/mol.114.097337.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (6)
Molecular Pharmacology
Vol. 87, Issue 6
1 Jun 2015
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Research ArticleArticle

Functional Selectivity of AngII Analogs

Ivana Domazet, Brian J. Holleran, Alexandra Richard, Camille Vandenberghe, Pierre Lavigne, Emanuel Escher, Richard Leduc and Gaétan Guillemette
Molecular Pharmacology June 1, 2015, 87 (6) 982-995; DOI: https://doi.org/10.1124/mol.114.097337

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Research ArticleArticle

Functional Selectivity of AngII Analogs

Ivana Domazet, Brian J. Holleran, Alexandra Richard, Camille Vandenberghe, Pierre Lavigne, Emanuel Escher, Richard Leduc and Gaétan Guillemette
Molecular Pharmacology June 1, 2015, 87 (6) 982-995; DOI: https://doi.org/10.1124/mol.114.097337
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