Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120)

Sparks, Steven M.; Chen, Grace; Collins, Jon L.; Danger, Dana P.; Dock, Steven T.; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher P.; Leesnitzer, M. Anthony; Liang, Xi; Maloney, Patrick; McCoy, David; Moncol, David; Rash, Vincent; Rimele, Thomas J.; Vulimiri, Padmaja; Way, James M.; Ross, Seamus

doi:10.1016/j.bmcl.2014.05.012

Cited by 93 publications

(94 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4A). Moreover, this effect of TUG-891 was blocked by coaddition of the FFA4 antagonist, compound 39 (Sparks et al, 2014) (Fig. 4, B and D), and this was also true for identification using the mFFA4 pSer 350 antiserum (Fig.…”

Section: Resultsmentioning

confidence: 61%

See 1 more Smart Citation

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

et al. 2016

View full text Add to dashboard Cite

It is established that long-chain free fatty acids including v-3 fatty acids mediate an array of biologic responses through members of the free fatty acid (FFA) receptor family, which includes FFA4. However, the signaling mechanisms and modes of regulation of this receptor class remain unclear. Here, we employed mass spectrometry to determine that phosphorylation of mouse (m) FFAR4 occurs at five serine and threonine residues clustered in two separable regions of the C-terminal tail, designated cluster 1 (Thr 347 , Thr 349 , and Ser 350 ) and cluster 2 (Ser 357 and Ser 361 ). Mutation of these phosphoacceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to extracellular signal regulated protein kinase 1 and 2 (ERK1/2) activation. Rather, an inhibitor of G q / 11 proteins completely prevented receptor signaling to ERK1/2. By contrast, the recruitment of arrestin 3, receptor internalization, and activation of Akt were regulated by mFFA4 phosphorylation. The analysis of mFFA4 phosphorylation-dependent signaling was extended further by selective mutations of the phosphoacceptor sites. Mutations within cluster 2 did not affect agonist activation of Akt but instead significantly compromised receptor internalization and arrestin 3 recruitment. Distinctly, mutation of the phosphoacceptor sites within cluster 1 had no effect on receptor internalization and had a less extensive effect on arrestin 3 recruitment but significantly uncoupled the receptor from Akt activation. These unique observations define differential effects on signaling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signaling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode) at the C terminus of the receptor.

show abstract

Section: Resultsmentioning

confidence: 61%

“…-2-yl)methoxy)phenyl)-propanoic acid] was synthesized as described previously (Shimpukade et al, 2012). Compound 39 was synthesized according to Sparks et al (2014). This compound is also known as AH 7614 (4-methyl-N-9H-xanthen-9-ylbenzenesulfonamide) and can be purchased from Tocris (Bristol, UK).…”

Section: Methodsmentioning

confidence: 99%

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

et al. 2016

View full text Add to dashboard Cite

show abstract

Section: Cellular Signaling and Pharmacological Tools For Ffa4mentioning

confidence: 98%

“…Sparks et al (2014) reported the identification of the selective FFA4 agonist GSK137647A and of the selective antagonist 39 (both diarylsulfonamides). The pEC 50 of GSK137647A was 6.3 for human FFA4 and the pIC 50 of antagonist 39 was 7.1 (Sparks et al, 2014). In addition, a selective high-affinity, orally available, small-molecule FFA4 agonist (cpdA) has also been developed and tested in vivo in high fat-diet induced animal model of obesity (Oh da et al, 2014).…”

Section: Cellular Signaling and Pharmacological Tools For Ffa4mentioning

confidence: 98%

Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages

2016

European Journal of Pharmacology

View full text Add to dashboard Cite

“…Therefore, GPR120 likely has a typical mechanism of activation observed in many GPCRs of the rhodopsin family. The validated GPR120 binding site, together with the improved homology model, could be further used for establishing the binding properties of a recently identified antagonist (Sparks et al 2014) and biased agonist (Li et al 2015). For instance, by introducing modifications in the cholecystokinin 2 (CCK2) receptor as well as in its biased antagonist suggested by modelling, Magnan and colleagues (Magnan et al 2013) were able to identify the key moiety in the ligand responsible for biased signalling and a microswitch of activation, involving M3.32 and Y7.43 that stabilizes the β-arrestin active state of the CCK2 receptor.…”

Section: ____________________________________________________________mentioning

confidence: 99%

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Tikhonova

2016

Free Fatty Acid Receptors

View full text Add to dashboard Cite

Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.

show abstract

Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120)

Cited by 93 publications

References 25 publications

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Contact Info

Product

Resources

About