Secretin targets interstitial cells of Cajal to regulate intestinal contractions.

Secretin is a gastrointestinal (GI) hormone that slows intestinal motility, an effect thought to be mediated through 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). Transcripts of secretin receptors (Sctr) are expressed abundantly by ICC in the deep muscular plexus (ICC-DMP). Secretin inhibits small intestinal contractions in the presence of the neurotoxin, tetrodotoxin (TTX) and suppresses excitatory enteric neurotransmission. The inhibitory effects of secretin occur through inhibition of Ca2+ transients in ICC-DMP, likely via Gαs-coupled cAMP production and PKA activation that leads to inhibition of IP3 receptors. Our results provide a novel concept for the role of ICC-DMP in small intestinal motility. ICC-DMP serve as integration hubs in which signaling from the enteric nervous system and hormones converge and integrate regulatory responses controlling intestinal motility. In the case of secretin, integrated responses may serve to slow intestinal transit to enhance digestion and absorption of nutrients.