ArticleThe Journal of biological chemistry2012
Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed.
- Therapeutic strategies for hypertension: exploring the role of microbiota-derived short-chain fatty acids in kidney physiology and development.Pediatric nephrology (Berlin, Germany) · 2026Review
- Short-Chain Fatty Acids Regulate Poultry Feed Intake via the Hypothalamus: Receptor-Mediated and Epigenetic Mechanisms.Animals : an open access journal from MDPI · 2026Review
- Free fatty acid receptor 2 allosterism is defined by cellular context.Cell communication and signaling : CCS · 2026Article
- Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120).Pharmacology & therapeutics · 2025Review
- Short-Chain Fatty Acids: Promising Therapeutic Targets for Respiratory Syncytial Virus Infection.Clinical reviews in allergy & immunology · 2025Review
- Regulatory mechanisms of the gut microbiota-short chain fatty acids signaling axis in slow transit constipation and progress in multi-target interventions.Frontiers in microbiology · 2025Review
- Article
- Free Fatty Acids and Free Fatty Acid Receptors: Role in Regulating Arterial Function.International journal of molecular sciences · 2024Review
- The Role of Short Chain Fatty Acids in Inflammation and Body Health.International journal of molecular sciences · 2024Review
- Structural basis for the ligand recognition and signaling of free fatty acid receptors.Science advances · 2024Article
- The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells.Frontiers in endocrinology · 2024Article
- Phosphorylation bar-coding of free fatty acid receptor 2 is generated in a tissue-specific manner.eLife · 2023Article
- Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists.Journal of medicinal chemistry · 2023Article
- Short-chain fatty acids: possible regulators of insulin secretion.Molecular and cellular biochemistry · 2023Review
- Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2022Review
- Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.Translational research : the journal of laboratory and clinical medicine · 2022Review
- Short-Chain Fatty Acid Receptors and Cardiovascular Function.International journal of molecular sciences · 2022Review
- Article
- Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model.Biomolecules & therapeutics · 2022Article
- Modulation of adipose tissue metabolism by microbial-derived metabolites.Frontiers in microbiology · 2022Review
4 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
Free fatty acid receptors 2 and 3 (FFA2 and FFA3) are G protein-coupled receptors for short chain free fatty acids (SCFAs). They respond to the same set of endogenous ligands but with distinct rank-order of potency such that acetate (C2) has been described as FFA2-selective, whereas propionate (C3) is non-selective. Although C2 was confirmed to be selective for human FFA2 over FFA3, this ligand was not selective between the mouse orthologs. Moreover, although C3 was indeed not selective between the human orthologs, it displayed clear selectivity for mouse FFA3 over mouse FFA2. This altered selectivity to C2 and C3 resulted from broad differences in SCFAs potency at the mouse orthologs. In studies to define the molecular basis for these observations, marked variation in ligand-independent constitutive activity was identified using a [(35)S]GTPγS assay. The orthologs with higher potency for the SCFAs, human FFA2 and mouse FFA3, displayed high constitutive activity in this assay, whereas the orthologs with lower potency for the agonist ligands, mouse FFA2 and human FFA3, did not. Sequence alignments of the second extracellular loop identified single negatively charged residues in FFA2 and FFA3 not conserved between species and predicted to form ionic lock interactions with arginine residues within the FFA2 or FFA3 agonist binding pocket to regulate constitutive activity and SCFA potency. Reciprocal mutation of these residues between species orthologs resulted in the induction (or repression) of constitutive activity and in most cases also yielded corresponding changes in SCFA potency.
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