Expression of GC-C, a receptor-guanylate cyclase, and its endogenous ligands uroguanylin and guanylin along the rostrocaudal axis of the intestine

Members of the receptor-guanylate cyclase (rGC) family possess an intracell ular catalytic domain that is regulated by an extracellular receptor domain . GC-C, an intestinally expressed rGC, was initially cloned by homology as an orphan receptor. The search for its Ligands has yielded three candidates : STa (a bacterial toxin that causes traveler's diarrhea) and the endogenou s peptides uroguanylin and guanylin. Here, by performing Northern and Weste rn blots, and by measuring [I-125]STa binding and STa-dependent elevation o f cGMP levels, we investigate whether the distribution of GC-C matches that of its endogenous ligands in the rat intestine. We establish that 1) urogu anylin is essentially restricted to small bowel; 2) guanylin is very low in proximal small bowel, increasing to prominent levels in distal small bowel and throughout colon; 3) GC-C messenger RNA and STa-binding sites are unif ormly expressed throughout the intestine; and 4) GC-C-mediated cGMP synthes is peaks at the proximal and distal extremes of the intestine (duodenum and colon), but is nearly absent in the middle (ileum). These observations sug gest that GC-C's activity may be posttranslationally regulated, demonstrate that the distribution of GC-C is appropriate to mediate the actions of bot h uroguanylin and guanylin, and help to refine current hypotheses about the physiological role(s) of these peptides.