INTRACELLULAR TRAFFICKING OF THE GLUT4 GLUCOSE-TRANSPORTER

GLUT4 function is dependent on cellular sorting and trafficking mechan isms that sequestration in the basal redistribution to the plasma memb rane in response to insulin stimulation. Structure-function studies ut ilizing chimeras of GLUT1 and GLUT4 have demonstrated that the 30-amin o-acid COOH-terminus of GLUT4 is necessary and sufficient for its sequ estration in intracellular membrane compartments in CHO, COS, L6 muscl e cells, and 3T3-L1 adipocytes. When expressed in CHO, COS or other ce lls that do not contain endogenous GLUT4, intracellular retention is e ntirely dependent on a double leucine motif contained within the GLUT4 COOH-terminus, which directs both rapid endocytosis and intracellular retention of expressed transporters. However, in 3T3-L1 adipocytes, a n additional motif or motifs in the 30-amino-acid COOH-terminus of GLU T4 may also operate to confer intracellular sequestration and insulin- mediated redistribution Kinetic analyses of GLUT4 internalization and recycling indicate that insulin enhances the exocytic rate constant of GLUT4, and causes a small decrease in its internalization rate. Recen t data suggest that phosphatidylinositol 3-kinases and their 3 phospho inositide products may be required for GLUT4 exocytosis, perhaps throu gh the regulation of components involved in membrane budding, fusion o r movement. New findings support the hypothesis that insulin causes ta rgeting of complexes containing insulin receptor substrate-1 and phosp hatidylinositol 3-kinase to the specialized GLUT4 sequestration compar tment, providing a possible mechanism for insulin action. (C) 1996 Aca demic Press Ltd