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FREE FATTY ACID RECEPTOR 3; FFAR3

FREE FATTY ACID RECEPTOR 3; FFAR3

Alternative titles; symbolsG PROTEIN-COUPLED RECEPTOR 41; GPR41HGNC Approved Gene Symbol: FFAR3Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 1...

Alternative titles; symbols

  • G PROTEIN-COUPLED RECEPTOR 41; GPR41

HGNC Approved Gene Symbol: FFAR3

Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,358,105-35,360,490 (from NCBI)

▼ Description
FFAR3 is a G protein-coupled receptor (GPCR) for microbiota-derived short-chain fatty acids, such as acetate, butyrate, and propionate (summary by Ang et al., 2018).

▼ Cloning and Expression
The physiologic responses to galanin (GAL; 137035) are mediated through specific membrane receptors called GALRs, which are members of the GPCR family. Sawzdargo et al. (1997) amplified human genomic DNA using PCR with degenerate primers based on conserved sequences of human and rat GALR1 (600377) and rat Galr2 (603691). One product contained a segment showing 100% homology to a portion of the 3-prime region of the human CD22 gene (107266). Sawzdargo et al. (1997) searched for open reading frames in this region and identified the GPR40 (603820) and GPR41 genes. GPR41 encodes a predicted 346-amino acid GPCR containing 7 transmembrane domains, 1 glycosylation site, 1 PKC phosphorylation site, 2 PKA/PKC phosphorylation sites, and 1 palmitoylation site, which is located in the C-terminal domain. The GPR41 protein shares 98% amino acid identity with GPR42 (603822) but little similarity with GALRs.

Liaw and Connolly (2009) noted that the GPR41 and GPR42 sequences reported by Sawzdargo et al. (1997) differ at only 6 amino acids. One difference, arg174 in GPR41 and trp174 in GPR42, was predicted to render GPR42 functionally inactive. However, Liaw and Connolly (2009) presented evidence that the 6 amino acid differences between GPR41 and GPR42, including that at residue 174, are polymorphisms rather than gene-specific differences. Of 202 GPR42 alleles genotyped, 123 (61%) had arg174, suggesting that GPR42 is a functional gene in a significant fraction of the human population. The authors also noted that current GPR41 expression data may represent a composite of GPR41 and GPR42 expression, as all standard techniques used to determine mRNA expression are unlikely to differentiate between GPR41 and GPR42 mRNA.

Using a transgenic reporter mouse, Nohr et al. (2015) showed that Ffar3 was expressed in superior cervical ganglion, as well as in thoracic sympathetic ganglia, prevertebral ganglia, vagal ganglia, dorsal root ganglia, and trigeminal ganglia. Immunohistochemical analysis showed that Ffar3 predominantly localized in granules in the perikaryon. The highest fraction of perikarya with Ffar3 expression was in sympathetic ganglia, and the lowest in trigeminal ganglion.

▼ Gene Structure
Sawzdargo et al. (1997) reported that the GPR41 gene has no introns.

▼ Mapping
Sawzdargo et al. (1997) reported that the GPR41 gene is located downstream of CD22, which was previously mapped to 19q13.1.

▼ Gene Function
Brown et al. (2003) and Le Poul et al. (2003) showed that short-chain fatty acids (SCFAs), such as propionate, bound human GPR41 and GPR43 (FFAR2; 603823).

Kimura et al. (2020) showed that maternal microbiota shapes the metabolic system of offspring in mice. They found that during pregnancy, short chain fatty acids (SCFAs) from the maternal gut microbiota were sensed by GPR41 and GPR43 in the sympathetic nerve, intestinal tract, and pancreas of the embryo, influencing prenatal development of the metabolic and neural systems. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers were highly susceptible to metabolic syndrome, even when reared under conventional conditions. Kimura et al. (2020) found that the maternal gut microbiota confers resistance to obesity in offspring via the SCFA-GPR41 and SCFA-GPR43 axes. These findings indicated that the maternal gut environment during pregnancy is a key contributor to metabolic programming of offspring to prevent metabolic syndrome.

Tang et al. (2015) showed that most beta cells in mouse pancreatic islets expressed fluorescence-tagged Ffar2 and Ffar3. In vitro studies revealed that mouse and human beta cells released acetate, most of which was derived from glucose metabolism, to inhibit insulin secretion in an autocrine and inhibitory fashion through Ffar2 and Ffar3. Analysis with knockout mice confirmed that acetate released from pancreatic islets reduced insulin secretion via Ffar2 and Ffar3, as deletion of both receptors led to greater insulin secretion and improved glucose tolerance in mice on a high-fat diet compared with controls. In mouse models of diabetes, increased acetate formation acted on Ffar2 and Ffar3 to inhibit proper glucose-stimulated insulin secretion by pancreatic islets.

Priyadarshini and Layden (2015) showed that Ffar3 -/- mice had increased insulin secretion from islets in response to increasing concentrations of glucose, as Ffar3 signaling negatively mediated insulin secretion. Ffar3 effects on glucose-stimulated insulin secretion were mediated through G-alpha-i (see GNAI1, 139310)/G-alpha-o (GNAO1; 139311) pathway. Transcriptome analysis revealed that Ffar3 deletion dramatically altered the islet transcriptome.

Using a proximity ligation assay, Ang et al. (2018) showed that endogenous FFAR2 and FFAR3 interacted to form a heteromer in human monocytes and macrophages. Further analysis revealed that FFAR2 and FFAR3 coexpressed in HEK293 cells formed homomers and FFAR2-FFAR3 heteromers. FFAR2-FFAR3 heteromerization elevated Ca(2+) signaling in HEK293 cells and attenuated cAMP inhibition. FFAR2-FFAR3 heteromerization also markedly enhanced recruitment of beta-arrestin-2 (ARRB2; 107941) to FFAR3 and enabled p38 (MAPK14; 600289) phosphorylation. FFAR2-FFAR3 heteromer-mediated signaling was sensitive to FFAR2 antagonism, G-alpha-q (GNAQ; 600998) inhibition, and G-alpha-i inhibition.

Tags: 19q13.12