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Lymphoguanylin: Cloning and Characterization of a Unique Member of the Guanylin Peptide Family

Harry S. Truman Memorial Veterans’ Hospital (L.R.F., S.L.E.) and the Departments of Pharmacology, Pathology and Anatomical Sciences, Physiology, and Biochemistry, School of Medicine and the Molecular Biology Program, Missouri University (L.R.F., S.L.E., X.F., R.M.L., Y.W., L.M.R., D.T.C., R.H.F., W.J.K.), Columbia, Missouri 65212

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

Guanylin and uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a uroguanylin complementary DNA (cDNA) detected uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preprouroguanylin and preproguanylin, respectively. A 15-amino acid, uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP.

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