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Signal."],"published-print":{"date-parts":[[2026,6,30]]},"abstract":"<jats:p>\n                    Individual G protein\u2013coupled receptors (GPCRs) are present on many cell types and regulate multiple physiological responses, making it necessary to design ligands that are selective for the targeted GPCR in a tissue-selective manner. Here, we found ligand-selective effects of the GPCR free fatty acid receptor 2 (FFAR2) mediated through differential activation of G\n                    <jats:sub>q<\/jats:sub>\n                    and G\n                    <jats:sub>i<\/jats:sub>\n                    family proteins in various tissues. These effects were elucidated with ago-allosteric regulators of FFAR2 that bind to overlapping sites (compound 187 and AZ1729) and to a distinct site (4-CMTB) in tissues from mice expressing a hemagglutinin-tagged human FFAR2 DREADD (designer receptor exclusively activated by designer drugs). The G\n                    <jats:sub>q<\/jats:sub>\n                    -activating ligand compound 187 stimulated the release of the gut hormones GLP-1 and PYY from colonic crypts and the secretion of insulin from pancreatic islets, effects that were prevented by the G\n                    <jats:sub>i<\/jats:sub>\n                    -biased ligand AZ1729. Both compound 187 and AZ1729 promoted G\n                    <jats:sub>i<\/jats:sub>\n                    -mediated neutrophil migration in bone marrow and antilipolytic effects in adipose tissue synergistically with an orthosteric DREADD agonist, whereas 4-CMTB was ineffective in both of these tissues. In contrast, 4-CMTB, alone or with the orthosteric agonist, produced G\n                    <jats:sub>q<\/jats:sub>\n                    signaling\u2013dependent effects in colonic crypts and pancreatic islets. These insights into the functional selectivity of allosteric ligands acting on the same GPCR may enable the development of physiologically specific therapeutics.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.aed9015","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:59:40Z","timestamp":1782842380000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric ligands with distinct properties uncover tissue-specific physiological regulation mediated by free fatty acid receptor 2"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-4307","authenticated-orcid":true,"given":"Natasja","family":"Barki","sequence":"first","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha M.","family":"Hassan Abdelmalik","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-8547","authenticated-orcid":true,"given":"Laura","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3796-1713","authenticated-orcid":true,"given":"Domonkos","family":"Dedeo","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6663-7520","authenticated-orcid":true,"given":"Paul","family":"Johnson","sequence":"additional","affiliation":[{"name":"School of Biodiversity, One Health &amp; Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Bolognini","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6946-3519","authenticated-orcid":true,"given":"Graeme","family":"Milligan","sequence":"additional","affiliation":[{"name":"Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211609200"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2025.108878"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-025-01183-w"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2023.2297811"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2016.03.017"},{"key":"e_1_3_2_7_2","first-page":"154","article-title":"Free fatty acid receptors 2 and 3 as microbial metabolite sensors to shape host health: Pharmacophysiological view","volume":"8","author":"Mishra S. 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