Will the original glucose transporter isoform please stand up!

Abstract

Monosaccharides enter cells by slow translipid bilayer diffusion by rapid, protein-mediated, cation-dependent cotransport and by rapid, protein-mediated equilibrative transport. This review addresses protein-mediated, equilibrative glucose transport catalyzed by GLUT1, the first equilibrative glucose transporter to be identified, purified, and cloned. GLUT1 is a polytopic, membranespanning protein that is one of 13 members of the human equilibrative glucose transport protein family. We review GLUT1 catalytic and ligand-binding properties and interpret these behaviors in the context of several putative mechanisms for protein-mediated transport. We conclude that no single model satisfactorily explains GLUT1 behavior. We then review GLUT1 topology, subunit architecture, and oligomeric structure and examine a new model for sugar transport that combines structural and kinetic analyses to satisfactorily reproduce GLUT1 behavior in human erythrocytes. We next review GLUT1 cell biology and the transcriptional and posttranscriptional regulation of GLUT1 expression in the context of development and in response to glucose perturbations and hypoxia in blood-tissue barriers. Emphasis is placed on transgenic GLUT1 overexpression and null mutant model systems, the latter serving as surrogates for the human GLUT1 deficiency syndrome. Finally, we review the role of GLUT1 in the absence or deficiency of a related isoform, GLUT3, toward establishing the physiological significance of coordination between these two isoforms. glucose transport; facilitated diffusion; major facilitator superfamily protein; bloodbrain barrier; placenta; diabetes; glucose transporter 1 deficiency syndrome; development MOST CELLS TRANSPORT SUGARS rapidly down the prevailing concentration gradient into or out of the cell. This equilibrative transport process is mediated by a family of sugar transporters called GLUTs. GLUT1 was the first glucose transporter isoform to be identified, purified (66, 132), and cloned (93) and is one of 13 proteins that comprise the human equilibrative glucose transporter family (63). GLUT1 is a membrane-spanning glycoprotein containing 12 transmembrane domains with a single N-glycosylation site, and its gene is located on chromosome 1 (1p35-31.3) (93). GLUT1 is expressed at the highest levels in the plasma membranes of proliferating cells forming the early developing embryo, in cells forming the blood-tissue barriers, in human erythrocytes and astrocytes, and in cardiac muscle (86). Having a catalytic turnover of ϳ1,200/s (115), glucose transporter 1 (GLUT1) provides an efficient pathway for cellular import and export of glucose. In addition, GLUT1 transports galactose and ascorbic acid (81,107). This review examines the catalytic properties, structure, molecular regulation, and physiology of GLUT1. GLUT1 CATALYTIC PROPERTIES Facilitated DiffusionThe cytoplasm of most cells equilibrates rapidly with nonmetabolizable extracellular sugars. This process is mediated by sugar transport proteins that catalyze unidirectional sugar up...

How does the chemical potential of the substrate drive a uniporter?

“…9 In such an experiment, the same set of loading and releasing concentrations of substrate (i.e., [S] L and [S] R ) is applied individually to both influx and efflux transports of the same uniporter. Yet, the transport rates in the two directions are usually different.…”

“…10 Interestingly, it is feasible that an energetically favorable, forward movement of a substrate-carrying uniporter is coupled with an energy-consuming, backward substrate-free conformational change (i.e., relaxation) of another. 7,9 Such a coupling would be equivalent to storing DG E . In this case, the transport speed is likely to be accelerated, because the ratelimiting transition-state energy barrier may be reduced (analogous to a double-cylinder engine).…”

“…Not surprisingly then, many uniporters form oligomers, maybe because evolution favored the state of cooperativity. 9 A counter-flow experiment (Fig. 2) can be considered as a special case of coupling, in which a substrate and its radioisotope-labeled counterpart (usually at the same concentration) may diffuse in opposite directions.…”

Resolution of the direct interaction with and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation

“…The kinetic properties of the glucose transport have been extensively studied, as red blood cells have provided a good experimental system due to the high expression of this carrier in their plasma membrane (14,15). Likewise, these investigations have revealed a set of different natural and artificial inhibitors of GLUT1, which do not share structural similarities with glucose (6, 9, 34, 36, 64).…”

“…GLUT1 resides mainly in the plasma membrane where it moves glucose to either side of the membrane depending on the direction of the glucose gradient (15). The kinetic properties of the glucose transport have been extensively studied, as red blood cells have provided a good experimental system due to the high expression of this carrier in their plasma membrane (14,15).…”