A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias.pdf (799.09 kB)
A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias.
journal contributionposted 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.
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.
CitationJournal of Biological Chemistry, 2016, 291 (36), pp. 18915-18931
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology
- VoR (Version of Record)
Published inJournal of Biological Chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology
G proteinG protein-coupled receptor (GPCR)allosteric regulationfatty acidinflammationAllosteric RegulationAnimalsColonDepsipeptidesGTP-Binding Protein alpha Subunits, Gi-GoGTP-Binding Protein alpha Subunits, Gq-G11HumansLipolysisMAP Kinase Signaling SystemMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NeutrophilsReceptors, Cell SurfaceReceptors, G-Protein-Coupled