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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bolognini, Dr Daniele and Moss, Catherine and Miller, Dr Ashley and Sergeev, Miss Eugenia and Kurowska-Stolarska, Professor 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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Journal of Biological Chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN: | 0021-9258 |
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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