MAMMALIAN NA+-INDEPENDENT SUGAR TRANSPORTERS AND THEIR HOMOLOGS IN OTHER ORGANISMS

Mammalian tissues contain at least six different, though related, passive sugar transporter isoforms (GLUTs 1-5 and 7). The mammalian transporters are members of a large family of homologous eukaryotic and prokaryotic transport proteins, which includes examples both of passive and of active, proton-linked transport systems. These proteins are predicted to consist of two bundles of six membrane-spanning alpha-helices. The precise roles of these putative helix bundles in the mechanism of transport remains unclear. However, both site-directed mutagenesis and photolabelling with substrate analogues have implicated the C-terminal bundle as the location of the substrate-binding site(s). Each of the mammalian sugar transporters has a distinctive tissue distribution and kinetic properties, that presumably reflect the different physiological roles of each isoform. For example, the GLUT4 isoform is found only in insulin-sensitive tissues such as fat and skeletal muscle, where it constantly recycles between the cell surface and an intracellular membranous compartment. The stimulation by insulin of glucose uptake in these tissues appears to involve primarily an increase in the rate at which the recycling transporter is exocytotically inserted into the plasma membrane. Great strides have recently been made in our understanding of the insulin signal transduction pathway. Of central importance appears to be the small GTP-binding protein Ras, which activates the mitogen-activated protein kinase cascade, but the relevant final target of this cascade remains mysterious. Similarly, investigation of the properties of transporter chimaeras is helping to identify the regions of the GLUT4 molecule that dictate its insulin-regulated trafficking.