Chemogenetic Approaches to Explore the Functions of Free Fatty Acid Receptor 2. (March 2021)

• Record Type: Journal Article
• Authors: Milligan, Graeme; Barki, Natasja; Tobin, Andrew B.
• Is Part Of: Trends in pharmacological sciences. Volume 42:Number 3(2021)
• Page Start: 191
• Page End: 202
• Publication Date: 2021-03
• Subjects: short-chain fatty acid -- G protein-coupled receptor -- designer receptor exclusively activated by designer drugs -- transgenic mice; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2020.12.003
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Short-chain fatty acids are generated in large amounts by the intestinal microbiota. They activate both the closely related G protein-coupled receptors free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3) that are considered therapeutic targets in diseases of immuno-metabolism. Limited and species-selective small-molecule pharmacology has restricted our understanding of the distinct roles of these receptors. Replacement of mouse FFA2 with a designer receptor exclusively activated by designer drug form of human FFA2 (hFFA2-DREADD) has allowed definition of specific roles of FFA2 in pharmacological and physiological studies conducted both ex vivo and in vivo, whilst overlay of murine disease models offers opportunities for therapeutic validation prior to human studies. Similar approaches can potentially be used to define roles of other poorly characterised receptors. Highlights: Building on the development and use of DREADD forms of muscarinic acetylcholine receptors a conceptually similar form of FFA2 has been produced. Because the described FFA2 antagonists have high affinity at human FFA2 but are essentially inactive at mouse and rat orthologues of the receptor, the FFA2-DREADD was generated from human FFA2. This FFA2-DREADD is activated by sorbic acid but not by SCFAs and blocked by FFA2 antagonists. Sorbic acid is a full agonist at the FFA2-DREADD and signalling mechanisms are identical to those produced by SCFAs at wild-type FFA2. Generation of a 'knock-in' transgenic mouse line in which the FFA2-DREADD replaced mouse FFA2 has allowed analysis of specific effects of FFA2 in both in vivo and ex vivo settings. Additional novel and selective activators of the FFA2-DREADD have been identified.