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A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias.

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journal contribution
posted on 2019-05-23, 10:20 authored by D Bolognini, CE Moss, K Nilsson, AU Petersson, I Donnelly, E Sergeev, GM König, E Kostenis, M Kurowska-Stolarska, A Miller, N Dekker, AB Tobin, G Milligan
The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points 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 signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, 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.

Funding

This work was supported by Biotechnology and Biosciences Research Council Grants BB/L027887/1 (to G. M. and A. M. M.) and BB/L02781X/1 (to A. B. T.) and German Research Foundation (DFG) (to G. M. K. and E. K.) for isolation and characterization of FR900359 Grant FOR2372. N.D., K.N., and A. U. P. are employees of AstraZeneca.

History

Citation

Journal of Biological Chemistry, 2016, 291 (36), pp. 18915-18931

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

  • VoR (Version of Record)

Published in

Journal of Biological Chemistry

Publisher

American Society for Biochemistry and Molecular Biology

eissn

1083-351X

Copyright date

2016

Available date

2019-05-23

Publisher version

http://www.jbc.org/content/291/36/18915

Language

en