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Secretin targets interstitial cells of Cajal to regulate intestinal motility

Bartlett, Allison1; Blair, Peter1; Sanders, Kenton1; Baker, Salah1

Research facility: National Institute of Diabetes and Digestive and Kidney Diseases
Published Aug 01, 2025 on Dryad. https://doi.org/10.5061/dryad.v6wwpzh6q

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Abstract

Secretin plays an important role in gastrointestinal (GI) physiology by stimulating bicarbonate and bile secretion to neutralize acidic chyme and aid in lipid absorption. Secretin also slows intestinal motility, an effect attributed to vagal afferent pathways. In this study, we show evidence for a novel function of secretin involving a non-neural mechanism mediated by interstitial cells of Cajal (ICC). Secretin receptors (SCTR) were found to be abundantly expressed by ICC in the deep muscular plexus (ICC-DMP) of the small intestine. Secretin reduced small intestinal contractions in the presence of tetrodotoxin (TTX) and suppressed cholinergic transmission. Ca2+ imaging demonstrated that the inhibitory effects of secretin occur through inhibition of Ca2+ transients in ICC-DMP, an effect previously linked to inhibition of intestinal contractions. SCTRs are linked to function via Gas, secretin increased cAMP levels in ICC-DMP, and responses were inhibited by a selective PKA antagonist. Our data suggest that PKA activation is in some way linked to inhibition of IP3 receptors, as the robust increase in Ca2+ transients in ICC-DMP due to uncaging of IP3 was blocked by secretin. Conclusions from these experiments outline a new concept for ICC-DMP: these cells serve as a focus point in which signaling from the enteric nervous system and hormones converge and integrate mechanisms regulating intestinal motility. In the case of secretin, this may result in slowing of intestinal transit to enhance digestion and absorption of nutrients.