Journal
FASEB JOURNAL
Volume 32, Issue 1, Pages 289-+Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700252RR
Keywords
GPCR heteromer; FFA2/GPR43; FFA3/GPR41
Categories
Funding
- National Medical Research Council [NMRC/CBRG/0055/2013]
- Ministry of Education [MoE 2013-T2-2-007, MoE R-154-000A31-114, MoE 2015-T2-1-122]
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Free fatty acid receptors 2 and 3(FFAR2/FFA2/GPR43andFFAR3/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 Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and beta-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), G(alpha q) inhibition(YM254890), or G(alpha i) 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.
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