title: Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle.
abstract: In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake. Here we show that TUG proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive TUG proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to TUG, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in TUG-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which TUG controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake.
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and.
authors.forename: Estifanos N
authors.initials: EN
authors.lastname: Habtemichael
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and.
authors.forename: Abel
authors.initials: A
authors.lastname: Alcázar-Román
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8020.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Rubin
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8020.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Grossi
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8020.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Belman
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8020.
authors.forename: Omar
authors.initials: O
authors.lastname: Julca
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Löffler
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Li
authors.affiliation: the Veterans Affairs San Diego Healthcare System and Department of Medicine, University of California, San Diego, California 92093, and.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and the Veterans Affairs Medical Center, West Haven, Connecticut 06516.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8020, jonathan.bogan@yale.edu.
authors.forename: Jonathan S
authors.identifier: http://orcid.org/0000-0001-6463-8466
authors.initials: JS
authors.lastname: Bogan
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D010122:Cystinyl Aminopeptidase / Q000378:metabolism; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D014667:Vasopressins / Q000378:metabolism*
chemical_list: C478539:Aspscr1 protein, mouse; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D014667:Vasopressins; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D005947:Glucose
keywords: aminopeptidase; glucose transporter type 4 (GLUT4); insulin; membrane trafficking; skeletal muscle; translocation; vasopressin