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Regulation of Insulin-Responsive Aminopeptidase Expression and Targeting in the Insulin-Responsive Vesicle Compartment of Glucose Transporter Isoform 4-Deficient Cardiomyocytes

Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics (E.D.A., C.G., S.B., M.P.), University of Utah School of Medicine, Salt Lake City, Utah 84112; Nuffield Department of Clinical Medicine (P.A.R.), University of Oxford, John Radcliffe Hospital II, Headington OX3 9DU, United Kingdom; and Department of Biochemistry (V.K., T.K., Z.X., K.V.K.), Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: E. Dale Abel, M.D., Ph.D., Division of Endocrinology, Metabolism and Diabetes, Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, 15 North 2030 East, Building 533, Room 3410B, Salt Lake City, Utah 84112. E-mail: dale.abel{at}hmbg.utah.edu.

In adipocytes and cardiac or skeletal muscle, glucose transporter isoform 4 (GLUT4) is targeted to insulin-responsive intracellular membrane vesicles (IRVs) that contain several membrane proteins, including insulin-responsive aminopeptidase (IRAP) that completely colocalizes with GLUT4 in basal and insulin-treated cells. Cardiac GLUT4 content is reduced by 65–85% in IRAP knockout mice, suggesting that IRAP may regulate the targeting or degradation of GLUT4. To determine whether GLUT4 is required for maintenance of IRAP content within IRVs, we studied the expression and cellular localization of IRAP and other GLUT4 vesicle-associated proteins, in hearts of mice with cardiac-specific deletion of GLUT4 (G4H–/–). In G4H–/– hearts, IRAP content was reduced by 60%, but the expression of other vesicle-associated proteins, namely cellugyrin, IGF-II/mannose-6-phosphate, and transferrin receptors, secretory carrier-associated membrane proteins and vesicle-associated membrane protein were unchanged. Using sucrose gradient centrifugation and cell surface biotinylation, we found that IRAP content in 50–80S vesicles where GLUT4 vesicles normally sediment was markedly depleted in G4H–/– hearts, and the remaining IRAP was found in the heavy membrane fraction. Although insulin caused a discernible increase in cell surface IRAP content of G4H–/– cardiomyocytes, cell surface IRAP remained 70% lower than insulin-stimulated controls. Immunoabsorption of intracellular vesicles with anticellugyrin antibodies revealed that IRAP content was reduced by 70% in both cellugyrin-positive and cellugyrin-negative vesicles. Endosomal recycling, as measured by transferrin receptor recycling was normal. Thus, GLUT4 and IRAP content of early endosome-derived sorting vesicles and of IRVs are coordinately regulated, and both proteins are required for maintenance of key constituents of these compartments in cardiac muscle cells in vivo.

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