Secretin Inhibits Small Intestinal Motility via Interstitial Cells of Cajal and cAMP Mechanisms

Background: Secretin is a member of the secretin-glucagon-vasoactive intestinal peptide hormone superfamily and is a multifunctional gastrointestinal- (GI) and neuro- peptide hormone. Secretin is primarily secreted postprandially from the crypts of Lieberkühn of duodenal enteroendocrine S cells into circulation where it reaches secretin receptor targets in the central nervous system and periphery. This dynamic hormone has been shown to act as a key signaling molecule in the regulation of digestion, metabolism and energy expenditure, water retention, reproduction, thermogenesis in adipose tissue, and in gastric and intestinal motility. Secretin’s canonical role in the GI tract is to stimulate the secretion of bicarbonate and bile from pancreatic ducts and bile ducts to neutralize acidic chyme exiting the stomach. Secretin has also been shown to slow intestinal motility, but its targets and mechanism of action is poorly understood. Aims: Several studies have proposed that secretin acts to slow intestinal motility in the intestines primarily through the many secretin receptors present on vagal afferents in the GI tract, here we discuss new data that suggests an alternate and complementary signaling pathway via interstitial cells of Cajal (ICC). ICC act as a liaison to facilitate a reduction in force of GI smooth muscle contraction through the activation of the secretin receptor (SCTR) and subsequent stimulation of the second messenger, cyclic adenosine monophosphate (cAMP). Here we provide evidence to show how ICC mediates changes in myogenic activity and motility in the small intestine. Methods: Spinning-disk confocal microscopy was used to monitor Ca2+ signaling in ICC from small intestinal muscles of GCaMP6f x KitiCre mice. Additionally, cAMP levels were evaluated using CAMPER mice. Intestinal muscle contractility was assessed using muscle strip myography experiments. Results: Secretin reduced small intestinal force of contraction in the presence of tetrodotoxin (TTX) and dampened the effect of cholinergic transmission. The secretin receptor (SCTR) is expressed primarily on ICC, specifically ICC within the deep muscular plexus (ICC-DMP) in the small intestine and Ca2+ imaging confirmed the effects are primarily localized within ICC-DMP. Secretin reduced carbachol-induced contractions and Ca2+ transients in ICC-DMP in response to electrical field stimulation (EFS) in the presence of LNNA (NO synthase inhibitor) and MRS2500 (P2Y1 antagonist). Secretin caused an increase in cAMP levels in ICC-DMP in muscles from Kit-iCre-CAMPER mice. PKA inhibitors rescued some of the effects of secretin on ICC-DMP Ca2+ signaling. Measurements of diameter change in large, intact, intestinal segments (4-5 cm) showed a significant decrease in response to Secretin. Conclusions: Secretin can inhibit small intestinal motility through the activation SCTRs on ICC-DMP via cAMP-mediated mechanisms. These results show how novel secretin targets on ICC influence GI muscles and reduce propulsive and segmental motility to facilitate nutrient absorption and digestion after a meal. Funding: This project was supported by R01 DK-120759 from the National Institute of Diabetes and digestive and Kidney (NIDDK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.