TRPV4 / NCX1 coupling regulates Ca ²⁺ ‐dependent cholecystokinin secretion from enteroendocrine cells to involve the

Abstract

Although stress can stimulate the vagus nerve via the brain–gut axis to induce enterohormone secretion from enteroendocrine cells (EECs), little is currently known about the roles of ion channels in the regulation of enterohormone secretion and the development of irritable bowel syndrome (IBS). We aimed to investigate whether transient receptor potential vanilloid 4 (TRPV4) channels and Na ⁺ /Ca ²⁺ exchanger 1 (NCX1) are critical for enterohormone secretion and whether they are involved in IBS. Ca ²⁺ imaging and patch‐clamp were applied to STC‐1. IBS‐diarrhea (IBS‐D) mouse model was established by wrap restraint stress (WRS). Western blot verified TRPV4 and NCX1 expressions in STC‐1; co‐immunoprecipitation demonstrated their physical interaction, and Ca ²⁺ imaging and patch‐clamp confirmed function and interaction. Carbachol (CCh), a stable analog of acetylcholine (ACh), induced Ca ²⁺ signaling and currents in EECs via a functional coupling of TRPV4 and NCX1. Moreover, intestinal cholecystokinin (CCK) transcripts in IBS‐D mice were significantly increased, and ACh enhanced intestinal CCK secretion in mice, all of which could be abolished by blockers of TRPV4, NCX1, and CCK receptors. Finally, these blockers alleviated the severity of IBS‐D in mice. We reveal a novel TRPV4/NCX1/Ca ²⁺ /CCK pathway in EECs, which is involved in the pathogenesis of IBS‐D. Targeting this pathway may hold promise for the prevention/treatment of IBS‐D.