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Signaling Pathways for Guanylin and Uroguanylin in the Digestive, Renal, Central Nervous, Reproductive, and Lymphoid Systems

The Truman Veterans Administration Medical Center (X.F., Y.W., R.M.L., S.L.E., L.R.F.) and the Departments of Pharmacology (X.F., Y.W., R.M.L., S.L.E.), Pathology and Anatomical Sciences (W.J.K.), and Physiology (R.H.F.), Missouri University School of Medicine, Columbia, Missouri 65212

Address all correspondence and requests for reprints to: Dr. Leonard R. Forte, Department of Pharmacology, University of Missouri School of Medicine, M-515 Medical Sciences Building, Columbia, Missouri 65212. E-mail: Leonard-R.-Forte{at}muccmail.missouri.edu

Guanylin and uroguanylin are peptides that stimulate membrane guanylate cyclases (GC) and regulate intestinal and renal function via cGMP. Complementary DNAs were isolated encoding opossum preproguanylin and a 279-amino acid portion of a receptor-guanylate cyclase expressed in opossum kidney (OK) cells (GC-OK). The tissue expression of messenger RNA transcripts for these signaling molecules were then compared. Northern and/or reverse transciption-PCR assays revealed that guanylin, uroguanylin, and GC-OK messenger RNAs are expressed in tissues within the digestive, renal, central nervous, reproductive, and lymphoid organ systems. Receptor autoradiography localized the receptors for uroguanylin and guanylin to renal proximal tubules and seminiferous tubules of testis. Synthetic guanylin and uroguanylin peptides activated the receptor-GCs in opossum kidney cortex and in cultured OK cells eliciting increased intracellular cGMP. Expression of agonist and receptor-GC signaling molecules provides a pathway for paracrine and/or autocrine regulation of cellular functions via cGMP in the digestive, renal, central nervous, reproductive, and lymphoid/immune organ systems. Uroguanylin also links the intestine and kidney in a potential endocrine axis that activates tubular receptor-GCs and influences renal function.

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