ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2012
Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 89 citations in OpenAlex.
- Short-chain fatty acids promote post-myocardial infarction cardiac repair via FFAR2-dependent suppression of osteoclast-like macrophage differentiation.Basic research in cardiology · 2026Article
- Short-chain fatty acids.Nature metabolism · 2026Review
- Acetate concentration correlates with MSNA in patients with resistant hypertension.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2025Article
- Article
- Endogenous ligands of bovine FFAR2/GPR43 display distinct pharmacological properties.Frontiers in cell and developmental biology · 2025Article
- Molecular recognition and activation mechanism of short-chain fatty acid receptors FFAR2/3.Cell research · 2024Article
- Structural basis for the ligand recognition and signaling of free fatty acid receptors.Science advances · 2024Article
- Phosphorylation bar-coding of free fatty acid receptor 2 is generated in a tissue-specific manner.eLife · 2023Article
- GPCR-mediated effects of fatty acids and bile acids on glucose homeostasis.Frontiers in endocrinology · 2023Review
- Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease.Aging and disease · 2022Review
- Chemogenetics of cell surface receptors: beyond genetic and pharmacological approaches.RSC chemical biology · 2022Review
- Article
- Dietary fatty acids in gut health: Absorption, metabolism and function.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2021Review
- Chemogenetic approaches to identify metabolically important GPCR signaling pathways: Therapeutic implications.Journal of neurochemistry · 2021Review
- Effects of Flavonoids Extracted fromAnimals : an open access journal from MDPI · 2021Article
- Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer.Frontiers in physiology · 2021Review
- Orthogonal Activation of Metabotropic Glutamate Receptor Using Coordination Chemogenetics.Frontiers in chemistry · 2021Article
- β-hydroxybutyrate and hydroxycarboxylic acid receptor 2 agonists activate the AKT, ERK and AMPK pathways, which are involved in bovine neutrophil chemotaxis.Scientific reports · 2020Article
- Chemogenetics defines receptor-mediated functions of short chain free fatty acids.Nature chemical biology · 2019Article
- DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDsACS pharmacology & translational science · 2018Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 4 countries.
Funding
Abstract
When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.