HETEROLOGOUS EXPRESSION OF RAB4 REDUCES GLUCOSE-TRANSPORT AND GLUT4 ABUNDANCE AT THE CELL-SURFACE IN OOCYTES

To evaluate the role of the small rab GTP-binding proteins in glucose transporter trafficking, we have heterologously co-expressed rab4 or r ab5 and GLUT4 or GLUT1 glucose transporters in Xenophus oocytes. Go-in jection of rab4 and GLUT4 cRNAs resulted in a dose-dependent decrease in glucose transport; this effect was specific for rab4, since co-inje ction of an inactive rab4 mutant or rab5 cRNA did not have any effect on glucose transport. The effect of rab4 was selective for GLUT4, sinc e no effect was detected in GLUT1-expressing oocytes. The inhibitory e ffect of rab4 on GLUT4-induced glucose transport was not the result of a change in overall cellular levels of GLUT4 glucose transporters. Ho wever, rab4 expression caused a marked decrease in the abundance of GL UT4 transporters present at the cell surface. Finally, rab4 and inhibi tors of PtdIns 3-kinase showed additive effects in decreasing glucose transport in GLUT4-expressing oocytes. We conclude that rab4 plays an important role in the regulation of the intracellular GLUT4 traffickin g pathway, by contributing to the intracellular retention of GLUT4 thr ough a PtdIns 3-kinase-independent mechanism.