FFAR3 Membrane Protein Introduction

Introduction of FFAR3

FFAR3, also known as G-protein coupled receptor 41 (GPR41), is a 38.6 kDa G protein-coupled receptor that consists of 346 amino acids. In humans, it is encoded by the FFAR3 gene which is located at the chromosome of 19q13.12. It is shown that FFAR3 is expressed in enteroendocrine cells, and the recent report also found it present in sympathetic neurons of the superior cervical ganglion. It is a protein-coding gene and its related pathways are peptide ligand-binding receptors and signals by G protein-coupled receptor. FFAR3 is activated by short-chain fatty acids (SCFAs), which engage the epigenetic regulation of inflammatory reactions via free fatty acid receptors (FFARs) and other SCFAs.

Function of FFAR3 Membrane Protein

As a Gαi-coupled receptor, it is activated by SCFAs primarily derived from dietary complex carbohydrate fibers in the large intestine as fermentation products of microbiota. FFAR3 and its family member free fatty acid receptor 2 (also known as FFAR2 or GPR43), are closely related, orphan seven-transmembrane proteins and both are receptors for SCFAs. SCFAs are not only an important energy source, but also functions as signaling molecules or chemical messengers in biology. These two can couple as an FFAR2-FFAR3 receptor heteromer via Gi/o pathways and both inhibit cAMP productions, while FFAR2, as opposed to FFAR3, is also able to bind efficiently through Gq. FFAR2 and FFAR3 subtypes are observed to be encoded in tandem at a single chromosomal locus. Their selectivity for SCFAs is rather similar since both of them are activated by two of the major SCFAs of propionate and butyrate.

Fig.1 Expression of short fatty acid receptor GPR41/FFAR3 in automatic and somatic sensory ganglia of the mouse. (Nøhr, 2015)

Application of FFAR3 Membrane Protein in Literature

1. Ang Z., et al. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. FASEB J. 2018, 32(1): 289-303. PubMed ID: 28883043
   
   

   The review is aimed to study that FFAR2 and FFAR3 interact to form a heteromer in primary human macrophages and monocytes and during heterologous expression in HEK293 cells by the fluorescence resonance energy transfer and bimolecular fluorescence complementation.

2. Muredda L., et al. IL-1β and TNFα inhibit GPR120 (FFAR4) and stimulate GPR84 (EX33) and GPR41 (FFAR3) fatty acid receptor expression in human adipocytes: implications for the anti-inflammatory action of n-3 fatty acids. Arch Physiol Biochem. 2018, 124(2): 97-108. PubMed ID: 28835131
   
   

   TNFα and IL-1β are able to induce a distinct reduction in GPR120 expression, while the GPR84 mRNA level is dramatically increased due to these cytokines, GPR41 stimulated as well. Rosiglitazone does not affect the GPR84 level, whereas GPR120 and GPR41 show an elevated expression.

3. Ang Z., et al. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Sci Rep. 2016, 6: 34145. PubMed ID: 27667443
   
   

   Knockout mice research involves the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3, in colitis, arthritis and asthma. Nevertheless, the association with human biology is unsure. Collectively, the result exhibited that SCFAs act by FFAR2/FFAR3 to modulate the human monocyte inflammation that is absent in mouse monocytes.

4. Priyadarshini M., et al. FFAR3 modulates insulin secretion and global gene expression in mouse islets. Islets. 2015, 7(2): e1045182. PubMed ID: 26091414
   
   

   The short chain fatty acid (SCFA) receptor, FFAR3 (Free fatty acid receptor-3) is expressed in pancreatic β cells, but its role in insulin secretion is uncertain. Data displayed that FFAR3 signaling is able to mediate glucose-stimulated insulin secretion by a sensitive Gαi/o pathway.

5. Nøhr M. K., et al. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience. 2015, 290: 126-137. PubMed ID: 25637492
   
   

   This article demonstrated that FFAR3 is expressed on sensory and postganglionic sympathetic neurons in both the autonomic and somatic peripheral nervous system. And SCFAs function not only by the enteroendocrine system but directly through modifying reflexes integrating the peripheral nervous and the gastrointestinal tract.

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Reference

1. Nøhr M K, et al. (2015). Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience. 290, 126-37.

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