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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/E1092    most recent 00440.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Wallis, M. G. Articles by Keller, S. R. Search for Related Content PubMed PubMed Citation Articles by Wallis, M. G. Articles by Keller, S. R.

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP

Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia

Submitted 7 July 2007 ; accepted in final form 3 August 2007

Insulin-regulated aminopeptidase (IRAP) is a membrane aminopeptidase and is homologous to the placental leucine aminopeptidase, P-LAP. IRAP has a wide distribution but has been best characterized in adipocytes and myocytes. In these cells, IRAP colocalizes with the glucose transporter GLUT4 to intracellular vesicles and, like GLUT4, translocates from these vesicles to the cell surface in response to insulin. Earlier studies demonstrated that purified IRAP cleaves several peptide hormones and that, concomitant with the appearance of IRAP at the surface of insulin-stimulated adipocytes, aminopeptidase activity toward extracellular substrates increases. In the present study, to identify in vivo substrates for IRAP, we tested potential substrates for cleavage by IRAP-deficient (IRAP^–/–) and control mice. We found that vasopressin and oxytocin were not processed from the NH₂ terminus by isolated IRAP^–/– adipocytes and skeletal muscles. Vasopressin was not cleaved from the NH₂ terminus after injection into IRAP^–/– mice and exhibited a threefold increased half-life in the circulation of IRAP^–/– mice. Consistent with this finding, endogenous plasma vasopressin levels were elevated twofold in IRAP^–/– mice, and vasopressin levels in IRAP^–/– brains, where plasma vasopressin originates, showed a compensatory decrease. We further established that insulin increased the clearance of vasopressin from control but not from IRAP^–/– mice. In conclusion, we have identified vasopressin as the first physiological substrate for IRAP. Changes in plasma and brain vasopressin levels in IRAP^–/– mice suggest a significant role for IRAP in regulating vasopressin. We have also uncovered a novel IRAP-dependent insulin effect: to acutely modify vasopressin.

peptide hormone cleavage; insulin-regulated aminopeptidase-deficient mice; insulin action