The long-term objective of this application is to examine the physiologic role of endogenous serotonin (5-HT) of mucosal origin in the regulation of intestinal mucosal transport. Studies of patients with carcinoid syndrome have demonstrated that circulating 5-HT, when elevated, is a potent secretagogue for water and chloride ion secretion. The hypothesis is that 5HT, which is released from enterochromaffin (EC) cells of the gut acts directly on adjacent crypt enterocytes, indirectly by release of neurotransmitters from enteric secretory or secreto-effector neurons, or via other secretagogues from adjacent cells (paracrine action) to induce secretion. The two main models are rat distal colon and human proximal jejunum. Accordingly, the specific aims are to characterize 1) the mechanisms of 5-HT release from the mucosa, using highperformance liquid chromatography with electrochemical detection from chambered mucosal sheets, enriched EC cells, or from vascularly perfused segments of intestine; 2) 5-HT receptor types and associated signal-transduction mechanisms in isolated, dispersed enterocytes and neural membranes, using radioligand binding techniques, measurement of intracellular messengers and RNA analysis techniques; 3) the neural and non-neural mechanisms of 5-HTinduced transport in chambered mucosal sheets under short-circuit conditions and in isolated enterocytes using radiolabeled ions, fluorescent techniques, and immunoassay measurements of second messengers; 4) the sensory enteric neuronal involvement in both 5-HT release, 5-HTinduced transport changes, and the enteric neuronal reflexes involved in mediation of secretory and motor responses to mucosal stimulation. This wlil be pursued in models of vascularly perfused intestine (both in vivo rat distal colon and isolated jejunal and colonic segments) with coordinated monitoring of net transport of sodium, chloride, and water, as well as real-time recording of circular and longitudinal motility. It is hoped that a better understanding of the physiologic role of intestinal mucosal 5-HT will lead to improved understanding of normal and abnormal human intestinal transport.
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