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Expression of GC-C, a Receptor-Guanylate Cyclase, and Its Endogenous Ligands Uroguanylin and Guanylin along the Rostrocaudal Axis of the Intestine¹

Department of Cell and Molecular Physiology, University of North Carolina (X.Q., S.P., M.F.G.), Chapel Hill, North Carolina 27599; and Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science (A.N., S.S.V.), Bangalore 560012, India

Address all correspondence and requests for reprints to: Dr. Michael F. Goy, Department of Cell and Molecular Physiology, Campus Box 7545, University of North Carolina, Chapel Hill, North Carolina USA 27599-7545. E-mail: mgoy{at}med.unc.edu

Members of the receptor-guanylate cyclase (rGC) family possess an intracellular 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 endogenous peptides uroguanylin and guanylin. Here, by performing Northern and Western blots, and by measuring [¹²⁵I]STa binding and STa-dependent elevation of cGMP levels, we investigate whether the distribution of GC-C matches that of its endogenous ligands in the rat intestine. We establish that 1) uroguanylin 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 uniformly expressed throughout the intestine; and 4) GC-C-mediated cGMP synthesis peaks at the proximal and distal extremes of the intestine (duodenum and colon), but is nearly absent in the middle (ileum). These observations suggest that GC-C’s activity may be posttranslationally regulated, demonstrate that the distribution of GC-C is appropriate to mediate the actions of both uroguanylin and guanylin, and help to refine current hypotheses about the physiological role(s) of these peptides.

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