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Postprandial blood glucose clearance is mediated by GLUT4 (glucose transporter 4) which is translocated from an intracellular storage pool to the plasma membrane in response to insulin. The nature of the intracellular storage pool of GLUT4 is not well understood. Immunofluorescence staining shows that, under basal conditions, the major population of GLUT4 resides in the perinuclear compartment. At the same time, biochemical fractionation reveals that GLUT4 is localized in IRVs (insulin-responsive vesicles). The relationship between the perinuclear GLUT4 compartment and the IRVs is not known. In the present study, we have exchanged the C-termini of GLUT4 and cellugyrin, another vesicular protein that is not localized in the IRVs and has no insulin response. We have found that GLUT4 with the cellugyrin C-terminus loses its specific perinuclear localization, whereas cellugyrin with the GLUT4 C-terminus acquires perinuclear localization and becomes co-localized with GLUT4. This, however, is not sufficient for the effective entry of the latter chimaera into the IRVs as only a small fraction of cellugyrin with the GLUT4 C-terminus is targeted to the IRVs and is translocated to the plasma membrane in response to insulin stimulation. We suggest that the perinuclear GLUT4 storage compartment comprises the IRVs and the donor membranes from which the IRVs originate. The C-terminus of GLUT4 is required for protein targeting to the perinuclear donor membranes, but not to the IRVs. [ABSTRACT FROM AUTHOR]