The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1

Smith, N.J., Stoddart, L.A., Devine, N.M., Jenkins, L. and Milligan, G. (2009) The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1. Journal of Biological Chemistry, 284(26), pp. 17527-17539. (doi: 10.1074/jbc.M109.012849) (PMID:19398560) (PMCID:PMC2719392)

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The endogenous ligands for Free Fatty Acid receptor 1 (FFA1) are medium- and longer-chain free fatty acids. However, a range of selective, small molecule ligands have recently been developed as tool compounds to explore the therapeutic potential of this receptor whilst clinically employed thiazolidinedione 'glitazone' drugs are also agonists at FFA1. Each of these classes of agonist was able to promote phosphorylation of the ERK1/2 MAP kinases in cells able to express human FFA1 on demand. However, although both lauric acid and the synthetic agonist GW9508X produced rapid and transient ERK1/2 MAP kinase phosphorylation, the thiazolidinedione rosiglitazone produced responses that were sustained for a substantially longer period. Despite this difference, the effects of each ligand required FFA1 and were transduced in each case predominantly via G proteins of the G{alpha}q/G{alpha}11 family. Different glitazone drugs also displayed markedly different efficacy and kinetics of sustainability of ERK1/2 MAP kinase phosphorylation. A number of orthosteric binding site mutants of FFA1 were generated and despite variations in changes of potency and efficacy of the three ligand classes in different functional end point assays, these were consistent with rosiglitazone also binding at the orthosteric site. Four distinct polymorphic variants of human FFA1 have been described. Despite previous indications that these display differences in function and pharmacology, they all responded in entirely equivalent ways to each of lauric acid, rosiglitazone and GW9508X in measures of each of ERK1/2 MAP kinase phosphorylation, enhancement of binding of [35S]GTP{gamma}S to G{alpha}q and elevation of intracellular [Ca2+], suggesting that individuals expressing each variant are likely to respond equivalently to orthosteric agonists of FFA1

Item Type:Articles
Glasgow Author(s) Enlighten ID:Walsh, Nicola and Milligan, Professor Graeme and Jenkins, Mrs Laura
Authors: Smith, N.J., Stoddart, L.A., Devine, N.M., Jenkins, L., and Milligan, G.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:27 April 2009

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