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Thrittene, Homologous with Somatostatin-28_(1–13), Is a Novel Peptide in Mammalian Gut and Circulation

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine (J.W.E., D.G.B., R.E.V., E.C.L., B.H.F.) and Department of Biological Structure (D.G.B.), University of Washington, Seattle, Washington 98195; Department of Veterans Affairs Puget Sound Health Care System (D.G.B.), Seattle, Washington 98108; ZymoGenetics (R.C.H., J.D.K., M.R.S.), Seattle, Washington 98102; Vollum Institute (M.J.L., M.R., V.O.-C.), Oregon Health Sciences University, Portland Oregon 97201-3098; and Division of Endocrinology (T.P.V., D.A.D.), University of Cincinnati, Ohio 45267-0547

Address all correspondence and requests for reprints to: David D’Alessio, M.D., University of Cincinnati, Division of Endocrinology, ML 0547, Cincinnati, Ohio 45267-0547. E-mail: . david.d'alessio{at}uc.edu

Preprosomatostatin is a gene expressed ubiquitously among vertebrates, and at least two duplications of this gene have occurred during evolution. Somatostatin-28 (S-28) and somatostatin-14 (S-14), C-terminal products of prosomatostatin (ProS), are differentially expressed in mammalian neurons, D cells, and enterocytes. One pathway for the generation of S-14 entails the excision of Arg¹³-Lys¹⁴ in S-28, leading to equivalent amounts of S-28_(1–12). Using an antiserum (F-4), directed to the N-terminal region of S-28 that does not react with S-28_(1–12), we detected a peptide, in addition to S-28 and ProS, that was present in human plasma and in the intestinal tract of rats and monkeys. This F-4 reacting peptide was purified from monkey ileum; and its amino acid sequence, molecular mass, and chromatographic characteristics conformed to those of S-28_(1–13), a peptide not described heretofore. When extracts of the small intestine were measured by RIA, there was a discordance in the ratio of peptides reacting with F-4 and those containing the C terminus of ProS, suggesting sites of synthesis for S-28_(1–13) distinct from those for S-14 and S-28. This was supported by immunocytochemistry, wherein F-4 reactivity was localized in gastrointestinal (GI) endocrine cells and a widespread plexus of neurons within the wall of the distal gut while immunoreactivity to C-terminal domains of S-14 and S-28 in these neurons was absent. Further, F-4 immunoreactivity persisted in similar GI endocrine cells and myenteric neurons in mice with a targeted deletion of the preprosomatostatin gene. We believe that these data suggest a novel peptide produced in the mammalian gut, homologous with the 13 residues of the proximal region of S-28 but not derived from the ProS gene. Pending characterization of the gene from which this peptide is derived, its distribution, and function, we have designated this peptide as thrittene. Its localization in both GI endocrine cells and gut neurons suggests that thrittene may function as both a hormone and neurotransmitter.

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