Water is absolutely necessary for the intestine to absorb food and dispose of wastes. The amount of water in the intestine is regulated by a small protein hormone produced in the wall of that organ. Too little water results in the release of this hormone, stimulating the cells lining the intestine to secrete water. Too much water results in a decrease in the release of this hormone, reducing water secretion into the intestine. However, it is unclear how this hormone stimulates intestinal cells to secrete water. It is known that the hormone binds to specific protein receptors on the surface of intestinal cells to stimulate secretion. Interestingly, there appear to be several receptors for this hormone with different structures and functions. These receptors appear to activate different signalling mechanisms in the cell. Which signalling pathway is responsible for triggering secretion is unknown. Also, which receptors are coupled to different signalling pathways has not been defined. Finally, the relationships between the different structures and functions of these receptors have not been examined. Studies outlined in this proposal involve the purification of these different receptors from intestinal cells. The structure and function of these isolated receptors will be defined and compared, to establish their relationship. The coupling of these different purified receptors to cellular signalling pathways will be established, to determine which receptor and signal pathway is involved in regulating intestinal secretion. These studies are significant because they will define basic mechanisms regulating a key intestinal function at the molecular level. In addition, the fundamental mechanisms coupling receptors and signalling pathways defined in these studies are generally applicable to the regulation of other organs, including the kidney and blood vessels.
