A novel allosteric activator of free fatty acid 2 receptor displays unique Gi-functional bias

Bolognini, D. et al. (2016) A novel allosteric activator of free fatty acid 2 receptor displays unique Gi-functional bias. Journal of Biological Chemistry, 291, pp. 18915-18931. (doi: 10.1074/jbc.M116.736157) (PMID:27385588) (PMCID:PMC5009265)

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The short chain fatty acid receptor FFA2 is able to stimulate signalling via both Gi and Gqv/G11-promoted pathways. These pathways are believed to control distinct physiological endpoints but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11. Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signalling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signalling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi-signalling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end-point transduced via activation of Gq/G11.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bolognini, Dr Daniele and Moss, Catherine and Miller, Dr Ashley and Sergeev, Miss Eugenia and Kurowska-Stolarska, Dr Mariola and Milligan, Professor Graeme and Tobin, Andrew and Donnelly, Mrs Iona
Authors: Bolognini, D., Moss, C. E., Nilsson, K., Petersson, A. U., Donnelly, I., Sergeev, E., König, G. M., Kostenis, E., Kurowska-Stolarska, M., Miller, A., Dekker, N., Tobin, A. B., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:05 July 2016
Copyright Holders:Copyright © 2016 American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Biological Chemistry 291:18915-18931
Publisher Policy:Reproduced under a creative commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659371Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1RI MOLECULAR CELL & SYSTEMS BIOLOGY