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Molecular Pharmacology

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Research ArticleArticle

The Agonism and Synergistic Potentiation of Weak Partial Agonists by Triethylamine in α1-Adrenergic Receptor Activation: Evidence for a Salt Bridge as the Initiating Process

James E. Porter, Stephanie E. Edelmann, David J. Waugh, Michael T. Piascik and Dianne M. Perez
Molecular Pharmacology April 1998, 53 (4) 766-771; DOI: https://doi.org/10.1124/mol.53.4.766
James E. Porter
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Stephanie E. Edelmann
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David J. Waugh
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Michael T. Piascik
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Dianne M. Perez
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Abstract

α1-adrenergic receptor (AR) activation is thought to be initiated by disruption of a constraining interhelical salt bridge (Porter et al., 1996). Disruption of this salt bridge is achieved through a competition for the aspartic acid residue in transmembrane domain three by the protonated amine of the endogenous ligand norepinephrine and a lysine residue in transmembrane domain seven. To further test this hypothesis, we investigated the possibility that a simple amine could mimic an important functional group of the endogenous ligand and break this α1-AR ionic constraint leading to agonism. Triethylamine (TEA) was able to generate concentration-dependent increases of soluble inositol phosphates in COS-1 cells transiently transfected with the hamster α1b-AR and in Rat-1 fibroblasts stably transfected with the human α1a-AR subtype. TEA was also able to synergistically potentiate the second messenger production by weak partial α1-AR agonists and this effect was fully inhibited by the α1-AR antagonist prazosin. However, this synergistic potentiation was not observed for full α1-AR agonists. Instead, TEA caused a parallel rightward shift of the dose-response curve, consistent with the properties of competitive antagonism. TEA specifically bound to a single population of α1-ARs with a K i of 28.7 ± 4.7 mm. In addition, the site of binding by TEA to the α1-AR is at the conserved aspartic acid residue in transmembrane domain three, which is part of the constraining salt bridge. These results indicate a direct interaction of TEA in the receptor agonist binding pocket that leads to a disruption of the constraining salt bridge, thereby initiating α1-AR activation.

Footnotes

    • Received October 30, 1997.
    • Accepted January 6, 1998.
  • Send reprint requests to: Dianne Perez, Ph.D., Dept. of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., FF30, Cleveland, OH 44195. E-mail:perezd{at}cesmtp.ccf.org

  • This work was supported by an Established Investigator Award from the National American Heart Association (D.M.P.). It was also supported in part by National Institutes of Health Grant RO1-HL52544 (D.M.P.), an unrestricted research grant from Glaxo-Wellcome (D.M.P.), a National American Heart Association Grant-in-Aid (M.T.P.), National Institutes of Health Grant RO1-HL38120 (M.T.P.), and an American Heart Association Postdoctoral Fellowship, Northeast Ohio Affiliate (J.E.P.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (4)
Molecular Pharmacology
Vol. 53, Issue 4
1 Apr 1998
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Research ArticleArticle

The Agonism and Synergistic Potentiation of Weak Partial Agonists by Triethylamine in α1-Adrenergic Receptor Activation: Evidence for a Salt Bridge as the Initiating Process

James E. Porter, Stephanie E. Edelmann, David J. Waugh, Michael T. Piascik and Dianne M. Perez
Molecular Pharmacology April 1, 1998, 53 (4) 766-771; DOI: https://doi.org/10.1124/mol.53.4.766

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Research ArticleArticle

The Agonism and Synergistic Potentiation of Weak Partial Agonists by Triethylamine in α1-Adrenergic Receptor Activation: Evidence for a Salt Bridge as the Initiating Process

James E. Porter, Stephanie E. Edelmann, David J. Waugh, Michael T. Piascik and Dianne M. Perez
Molecular Pharmacology April 1, 1998, 53 (4) 766-771; DOI: https://doi.org/10.1124/mol.53.4.766
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