INSULIN-STIMULATED GLUT4 GLUCOSE-TRANSPORTER RECYCLING - A PROBLEM INMEMBRANE-PROTEIN SUBCELLULAR TRAFFICKING THROUGH MULTIPLE POOLS

The subcellular trafficking of GLUT4 in isolated rat adipose cells and 3T3-L1 adipocytes exhibits many of the properties observed in regulat ed secretory processes and neurosecretion. GLUT4 is sorted and sequest ered from endosomes into a specialized secretory compartment in the ba sal state and the initial stimulation of its exocytosis by insulin is more rapid than its recycling through the endosomes and secretory comp artment during the steady-state response to insulin. We present a math ematical analysis which shows that this behavior is inconsistent with a simple 2-pool model with one plasma membrane and one intracellular c ompartment, but that a 3-pool model, with two intracellular compartmen ts, can simulate these properties. We extend this model to include the presence of occluded pools in the plasma membrane. Our analysis compa res the behavior expected when these occluded pools are precursors in stimulation and/or clathrin-associated-like intermediates in endocytos is. The presence of a precursor occluded pool can account for a lag be tween the appearance of GLUT4 in the membrane and before the full stim ulation of glucose transport activity. The analysis also shows that si nce the pool size of the occluded GLUT4 is relatively small, the forma tion of endocytic occluded intermediates such as GLUT4 in clathrin-coa ted pits is likely to be slow compared with the rate of endocytosis of the coated vesicles.