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  • Z-LEHD-FMK GPR co localizes with ghrelin in the duodenum gus

    2021-09-06

    GPR120 co-localizes with ghrelin in the duodenum [17], α-gustducin in the small intestine and type II taste bud cells 18, 19, neuropeptide Y centrally in the arcuate nucleus [20] and glucagon-like peptide 1 (GLP-1) in the colon and circumvallate papillae taste bud cells 6, 21, 22. Interestingly GPR120 was also found to be co-expressed with other receptors for FAs including GPR43 in the proximal colon of mice [19] and GPR40 in STC-1 intestinal cells [6]. These distinct patterns of expression and co-localization are likely reflective of the functions of GPR120 discussed below.
    Ligands for GPR120 GPR120 is a receptor specific for LCFAs [6]. FAs are generated during lipolysis [23]. Free FAs released into the plasma then circulate and not only provide substrate for energy production but importantly also act as endogenous ligands to modulate the expression of genes and proteins that regulate a diverse range of physiological and pathophysiogical functions including those related to energy homeostasis 24, 25. Studies to date have shown that unsaturated FAs with a carbon chain length of 16–22, including the omega 3 FAs alpha-linolenic Z-LEHD-FMK (α-LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid act as endogenous ligands for GPR120 6, 8. Of these, α-LA and DHA appear most potent at GPR120 6, 8. In the search for small molecule agonists for GPR120, initial studies identified a derivative of peroxisome-proliferator-activated receptor (PPAR) γ [26], namely GW9508, as an agonist for GPR120 [27]. However, the dual specificity of GW9508 for GPR40 and GPR120 [27] presents as a confounding variable in the interpretation of results in studies using GW9508 as a result of off-target effects at the other receptor. Further research identified several other potential agonists for GPR120 including the plant-derived compound grifolic acid, which acts as a partial selective GPR120 agonist [28], NCG21 [29] and GSK137647A [22], which are reported as selective at GPR120 (Table 2). Most recently, TUG891 (4-[(4-fluoro-4′-methyl[1,1′-biphenyl]-2-yl)methoxy]-benzenepropanoic acid) has been made commercially available as a GPR120 agonist by Tocris Bioscience and R&D Systems. TUG891 is reported to be potent and selective for GPR120 demonstrating greater selectivity and potency to GPR120 than GPR40 30, 31. However, Hudson et al.[31] also demonstrate phosphorylation and desensitization of GPR120 following stimulation with TUG891, suggesting that tachyphylaxis could complicate the use of this compound therapeutically. Furthermore, the work of Hudson et al.[31] also suggests that interspecies differences in the selectivity of TUG891 to GPR120 over GPR40 exist with a substantial loss of GPR120 selectivity when cells expressing mouse GPR120 were challenged with the agonist. This limits the value of preclinical in vivo studies in mice regarding the activation of GPR120 with TUG891. Interestingly, the GPR40 antagonist GW1100 was reported as being without effect on GPR120 [31] and thus, via selectively inhibiting GPR40, GW1100 used in conjunction with TUG891 might be of benefit in attributing specific effects of TUG891 to GPR120. Because the development of a potent and selective GPR120 agonist is indispensable in the development of GPR120 as a druggable receptor, the availability of TUG891 is a promising step forward in investigating the functions of GPR120 specifically. However, given the interspecies loss of selectivity of TUG891 for GPR120, further research is needed to optimize and characterize fully the functional effects of TUG891 and other potential agonistic compounds at GPR120.
    GPR120 signaling GPR120 has been shown to couple to Gαq and β-arrestin 2 mediated pathways 6, 8 (Fig. 2). Coupling of GPR120 induces increases in intracellular calcium transients 6, 10 and is without effect on intracellular cyclic adenosine monophosphate concentration [6]. Activation of GPR120 has been shown to lead to receptor internalization [8]. Oh et al.[8] show that, in RAW 264.7 cells, DHA stimulation induced translocation of β-arrestin 2 to the plasma membrane where it co-localizes with GPR120. Further treatment with DHA led to internalization of GPR120, which was then observed to co-localize with cytosolic β-arrestin 2 [8]. This suggests that β-arrestin 2 is implicated in GPR120 internalization. Abrogation of β-arrestin 2 signaling via selective RNA interference was shown to attenuate DHA-mediated anti-inflammatory effects [8] suggesting that, upon binding to GPR120, this LCFA exerts its effects via β-arrestin 2 signaling. However, the dual coupling of GPR120 to Gαq and β-arrestin 2 might account for the divergence in the reported functions of this receptor. Moreover, although not fully characterized at present, it is likely that GPR120-mediated signaling is different in distinct tissue types. Therefore, extrapolating findings from one tissue to another may be fraught. Thus, further research into the tissue-specific effectors of GPR120 agonism will be important in understanding how pharmaceutical agents that target a distinct signaling pathway could be developed for the treatment of specific disease states.