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FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing

Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota–derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR...

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Detalles Bibliográficos
Autores principales: Ang, Zhiwei, Xiong, Ding, Wu, Min, Ding, Jeak Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Federation of American Societies for Experimental Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731126/
https://www.ncbi.nlm.nih.gov/pubmed/28883043
http://dx.doi.org/10.1096/fj.201700252RR
Descripción
Sumario:Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota–derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca(2+) signaling (1.5-fold increase relative to homomeric FFAR2) and β-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), G(αq) inhibition (YM254890), or G(αi) inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890-sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers—a novel pathway for drug targeting.—Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.