GLUT1 Structure, Function and Trafficking-Regulation by Cellular Redox and Metabolic Status

The Glucose Transporters (GLUTs) comprise a family of 14 integral membrane proteins that catalyzes the facilitated diffusion of hexose and pentose sugars into and out of human cells. GLUT1 (the major GLUT expressed in astrocytes, smooth muscle, photoreceptors and blood-tissue barrier endothelia cells) and GLUTs 3 and 4 (the major transporters expressed in neurons) are glucose/galactose and dehydroascorbate (DHA) transporters. This presentation examines our understanding of GLUT secondary, tertiary and quaternary structures, how they influence substrate specificity and transport efficiency and how they are in turn affected by cellular redox and metabolic status. We examine how cellular glucose transport activity is acutely regulated by nucleotide-dependent modulation of GLUT1 intrinsic activity and trafficking between intracellular and cell surface membranes with specific reference to glucose transport across blood tissue barriers. Intrinsic activity is allosterically regulated via nucleotide interaction with a GLUT1 purine nucleotide binding site which is a potential site for small molecule targeting. GLUT1 trafficking is regulated by the metabolic master switch AMPK and appears to involve AMPK-inhibition of GLUT1 endocytosis. We then discuss the use of a high throughput, small molecule screen to identify activators and inhibitors of GLUT1 activity and membrane trafficking. We conclude that GLUT1-mediated sugar transport is a key rate-limiting step in glycolysis, is subject to a multiplicity of regulatory mechanisms that affect transport structure, activity and trafficking which, in turn, are targets for pharmacologic intervention.