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Molecular Pharmacology

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Research ArticleArticle

Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2

Taeweon Lee, Ralf Schwandner, Gayathri Swaminath, Jennifer Weiszmann, Mario Cardozo, Joanne Greenberg, Peter Jaeckel, Hongfei Ge, Yingcai Wang, Xianyun Jiao, Jiwen Liu, Frank Kayser, Hui Tian and Yang Li
Molecular Pharmacology December 2008, 74 (6) 1599-1609; DOI: https://doi.org/10.1124/mol.108.049536
Taeweon Lee
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Ralf Schwandner
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Gayathri Swaminath
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Jennifer Weiszmann
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Mario Cardozo
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Joanne Greenberg
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Peter Jaeckel
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Hongfei Ge
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Yingcai Wang
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Xianyun Jiao
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Jiwen Liu
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Frank Kayser
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Hui Tian
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Yang Li
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Abstract

FFA2 (GPR43) has been identified as a receptor for short-chain fatty acids (SCFAs) that include acetate and propionate. FFA2 is highly expressed in islets, a subset of immune cells, and adipocytes. Although the potential roles of FFA2 activation in these tissues have previously been described, the physiological functions are still unclear. The potency for SCFAs on FFA2 is low, in the high micromolar to millimolar concentrations. To identify better pharmacological tools to study receptor function, we used high-throughput screening (HTS) to discover a series of small molecule phenylacetamides as novel and more potent FFA2 agonists. This series is specific for FFA2 over FFA1 (GPR40) and FFA3 (GPR41), and it is able to activate both the Gαq and Gαi pathways in vitro on Chinese hamster ovary cells stably expressing FFA2. Treatment of adipocytes with these compounds also resulted in Gαi-dependent inhibition of lipolysis similar to that of endogenous ligands (SCFAs). It is noteworthy that these compounds not only acted as FFA2 agonists but also exhibited positive cooperativity with acetate or propionate. The observed allosteric modulation was consistent in all the functional assays that we have explored, including cAMP, calcium mobilization, guanosine 5′-[γ-thio]triphosphate binding, and lipolysis. Molecular modeling analysis of FFA2 based on human β2-adrenergic receptor structure revealed potential nonoverlapping binding sites for the endogenous and synthetic ligands, further providing insight into the binding pocket for the allosteric interactions. This is the first report describing the identification of novel allosteric modulators with agonist activity for FFA2, and these compounds may serve as tools for further unraveling the physiological functions of the receptor and its involvement in various diseases.

Footnotes

  • T.L., R.S., G.S., and J.W. contributed equally to this work.

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; SCFA, short-chain fatty acid; HTS, high-throughput screen; GTPγS, guanosine 5′-[γ-thio]triphosphate; DMSO, dimethyl sulfoxide; CHO, Chinese hamster ovary; TM, transmembrane domain; PTX, pertussis toxin; CGP7930, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; RLU, relative luminescence units.

    • Received June 6, 2008.
    • Accepted September 25, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (6)
Molecular Pharmacology
Vol. 74, Issue 6
1 Dec 2008
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Research ArticleArticle

Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2

Taeweon Lee, Ralf Schwandner, Gayathri Swaminath, Jennifer Weiszmann, Mario Cardozo, Joanne Greenberg, Peter Jaeckel, Hongfei Ge, Yingcai Wang, Xianyun Jiao, Jiwen Liu, Frank Kayser, Hui Tian and Yang Li
Molecular Pharmacology December 1, 2008, 74 (6) 1599-1609; DOI: https://doi.org/10.1124/mol.108.049536

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Research ArticleArticle

Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2

Taeweon Lee, Ralf Schwandner, Gayathri Swaminath, Jennifer Weiszmann, Mario Cardozo, Joanne Greenberg, Peter Jaeckel, Hongfei Ge, Yingcai Wang, Xianyun Jiao, Jiwen Liu, Frank Kayser, Hui Tian and Yang Li
Molecular Pharmacology December 1, 2008, 74 (6) 1599-1609; DOI: https://doi.org/10.1124/mol.108.049536
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