Neural FFA3 activation inversely regulates anion secretion evoked by nicotinic ACh receptor activation in rat proximal colon

Abstract

The proximal colonic mucosa is constantly exposed to high concentrations of microbially-produced short-chain fatty acids (SCFA). Although luminal SCFA evoke electrogenic anion secretion and smooth muscle contractility via neural and non-neural cholinergic pathways in the colon, the involvement of the SCFA receptor FFA3, one of the free fatty acid receptor (FFAR) family members, has not been clarified. We investigated the contribution of FFA3 to cholinergic-mediated secretory responses in rat proximal colon. FFA3 was immunolocalized to enteroendocrine cells and to the enteric neural plexuses. Most FFA3-immunoreactive nerve fibres and nerve endings were cholinergic, colocalized with PGP9.5, the vesicular ACh transporter, and the high-affinity choline transporter CHT1. In Ussing chambered mucosa-submucosa preparations (including the submucosal plexus) of rat proximal colon, carbachol (CCh)-induced Cl⁻ secretion was decreased by TTX, hexamethonium, and serosal FFA3 agonists acetate or propionate, but not by an inactive analogue 3-chloropropionate. Serosal application of the selective FFA3 agonist (N-[2-methylphenyl]-[4-furan-3-yl]-2-methyl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxamide; MQC) dose-dependently suppressed the response to CCh, but not to forskolin, with an IC₅₀ of 13 μM. Pretreatment with MQC inhibited nicotine-evoked, but not bethanechol-evoked secretion. The inhibitory effect of MQC was reversed by pretreatment with pertussis toxin, indicating that FFA3 acts via the G_i/o pathway. Luminal propionate induced Cl⁻ secretion via the cholinergic pathway, which was reduced by MQC, as well as by TTX, hexamethonium, or by removal of the submucosal plexus. These results suggest that SCFA-FFA3 pathway has a novel antisecretory function in that it inhibits cholinergic neural reflexes in the enteric nervous system.

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