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    • The ability of FFA to

    2022-05-17

    The ability of FFA4 to elevate intracellular levels of Ca2+5, 38, 39, 40 provided early predictions of a key role of the phosphoinositidase C-linked G proteins Gq and/or G11 in transduction of signals from this receptor, while later studies that examined production of inositol phosphates [41] provided further support. The importance of this group of G proteins to key aspects of FFA4 function has been confirmed by the ability of selective Gq/G11 inhibitors to block such signals [41]. When expressed in HEK293 entinostat australia that had been genome-edited to lack expression of both Gq and G11, FFA4 was unable to induce elevation of either inositol phosphates or intracellular Ca2+ levels [41]. Although this appears to be the dominant mode of G protein-mediated signalling for FFA4 (Figure 1), several reports suggest that treatment with pertussis toxin eliminates the ability of this receptor to regulate the release of the satiety hormone ghrelin [42] (Figure 1) and also the release of somatostatin from delta cells of the pancreas [43]. This indicates a key role for Gi-family G proteins in these processes. Segerstolpe et al.[44] noted expression of mRNA encoding FFA4 in delta cells isolated from both healthy individuals and those with T2DM that was higher than expression of this receptor in pancreatic β cells derived from the same individuals. Interestingly, and by contrast, FFA4 mRNA expression was not detected in either α or γ cells [44]. This expression profile in cell subtypes may have substantial significance and could be exploited if FFA4 agonists can be identified that show ‘bias’ between promoting signalling via Gq/11 and Gi-family G proteins. In initial deorphanisation studies, Hirasawa et al.[5] used measures of the internalisation of FFA4 from the surface of transfected cells. Such agonist-induced internalisation of FFA4 is both robust and extensive 39, 40 and, at least in the context of HEK293 cells, is almost entirely dependent on interactions with an arrestin adapter protein [41] (Figure 1). Non-canonical, non-G-protein-mediated, signalling role(s) of such a FFA4/arrestin complex remain to be fully defined. For example, although arrestins are often linked to aspects of the temporal profile of GPCR-mediated regulation of the ERK1/2 MAP kinases, Alvarez-Curto et al.[41] did not identify a substantial role for arrestins in FFA4-mediated phosphorylation of ERK1/2 when using HEK293 cells genome-edited to lack expression of either Gαq plus Gα11, or of β-arrestin 1+β-arrestin 2. Moreover, the key role of arrestins in FFA4 signalling in these cell backgrounds was their more traditional role in acting to desensitise G protein-mediated signalling because their elimination resulted in Ca2+ ‘spikes’ being generated repetitively with maintained exposure to an agonist [41]. Despite this, the now well-established anti-inflammatory roles of FFA4 expressed within immune cell populations where, in mice, particularly high levels are reported in thymus CD8+ dendritic cells and in lung-resident macrophages (Immunological Genome Project) has focused attention on potential contributions of interactions of FFA4-associated arrestins with the transforming growth factor beta (TGF-β)-activated kinase 1 binding protein 1 (TAB-1). This is believed to limit TAB-1 interacting with TGF-β-activated kinase 1 (TAK1), a complex that is important for transmitting signals from activated cell surface Toll-like receptors (TLRs), and the receptor for tumour necrosis factor alpha (TNFα), for the production and release of proinflammatory mediators [45]. The sustained interaction between agonist-occupied FFA4 and an arrestin is based on agonist-promoted phosphorylation of several serine and threonine residues located in the intracellular, C terminal of the receptor 46, 47, 48 (Figure 2). Conversion of these residues to non-hydroxyl amino acids greatly reduces such interactions, while production of antisera that recognise amino acids within the C-terminal region specifically only when they are phosphorylated 41, 47, 48 has provided reagents able to assess the state of receptor activation. In humans, splice variation within the third intracellular loop of FFA4 produces a ‘long’ isoform containing 16 additional amino acids [49]. Although expression of the long variant seems to be restricted, it appears to act as a ‘biased’ receptor, unable to engage with G protein-mediated signalling systems, but is able to interact with β-arrestins as the short isoform and to undergo internalisation in an agonist-dependent manner [39]. The broader implications of this remain unclear because there is no obvious tissue situation in which the long isoform is uniquely expressed and in which only β-arrestin- or non-G protein-mediated signalling might therefore be anticipated.