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Research ArticleArticle

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Bronwyn A. Evans, Natalie Broxton, Jon Merlin, Masaaki Sato, Dana S. Hutchinson, Arthur Christopoulos and Roger J. Summers
Molecular Pharmacology February 2011, 79 (2) 298-307; DOI: https://doi.org/10.1124/mol.110.067454
Bronwyn A. Evans
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Natalie Broxton
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Jon Merlin
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Masaaki Sato
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Dana S. Hutchinson
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Arthur Christopoulos
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Roger J. Summers
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This article has a correction. Please see:

  • Correction - March 01, 2011

Abstract

Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting interaction between distinct receptor conformational states and particular Gα subunits or alternative signaling proteins. We have tested the capacity of agonists to stimulate Ca2+ release, cAMP accumulation, and changes in extracellular acidification rate (ECAR) at the human α1A-adrenoceptor. Signaling bias factors were determined by novel application of an operational model of agonism and compared with the reference endogenous agonist norepinephrine; values significantly different from 1.0 indicated an agonist that promoted receptor conformations distinct from that favored by norepinephrine. Oxymetazoline was a full agonist for ECAR and a partial agonist for Ca2+ release (bias factor 8.2) but failed to stimulate cAMP production. Phenylephrine showed substantial bias toward ECAR versus Ca2+ release or cAMP accumulation (bias factors 21 and 33, respectively) but did not display bias between Ca2+ and cAMP pathways. Cirazoline and N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide (A61603) displayed bias toward cAMP relative to Ca2+ release (bias factors of 7.4 and 8.6). It is noteworthy that epinephrine, a second endogenous adrenoceptor agonist, did not display bias relative to norepinephrine. Our finding that phenylephrine displayed significant signaling bias, despite being highly similar in structure to epinephrine, indicates that subtle differences in agonist-receptor interaction can affect conformational changes in cytoplasmic domains and thereby modulate the repertoire of effector proteins that are activated.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was funded by the National Health and Medical Research Council (NHMRC) of Australia [Program Grant 519461]; an NHMRC Senior Research Fellowship (to A.C.); and an NHMRC Career Development Award (to D.S.H.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.067454.

  • ABBREVIATIONS:

    ECAR
    extracellular acidification rate
    IBMX
    3-isobutyl-1-methylxanthine
    AR
    adrenoceptor
    CHO
    Chinese hamster ovary
    FBS
    fetal bovine serum
    HBSS
    Hanks' balanced saline solution
    A61603
    N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide
    A23187
    calcimycin
    U73122
    1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione
    TM
    transmembrane domain.

  • Received July 8, 2010.
  • Accepted October 26, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Bronwyn A. Evans, Natalie Broxton, Jon Merlin, Masaaki Sato, Dana S. Hutchinson, Arthur Christopoulos and Roger J. Summers
Molecular Pharmacology February 1, 2011, 79 (2) 298-307; DOI: https://doi.org/10.1124/mol.110.067454

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Research ArticleArticle

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Bronwyn A. Evans, Natalie Broxton, Jon Merlin, Masaaki Sato, Dana S. Hutchinson, Arthur Christopoulos and Roger J. Summers
Molecular Pharmacology February 1, 2011, 79 (2) 298-307; DOI: https://doi.org/10.1124/mol.110.067454
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