Glucose transporter, type 4 (GLUT4) (Glc_transpt_4)
Type: Family

The ability to transport glucose across the plasma membrane is a feature common to nearly all cells, from simple bacteria through to highly specialised mammalian neurones. Facilitative sugar transport is mediated by members of the GLUT transporter family, which form an aqueous pore across the membrane through which sugars can move in a passive (i.e., energy-independent) manner; in consequence, they can only transport sugars down their concentration gradient. The GLUT family of glycosylated transmembrane proteins are predicted to span the membrane 12 times with both amino-and carboxyl-termini located in the cytosol. On the basis of sequence homology and structural similarity, three subclasses of sugar transporters have been defined: Class I (GLUTs 1-4) are glucose transporters; Class II (GLUTs 5, 7, 9 and 11) are fructose transporters; and Class III (GLUTs 6, 8, 10, 12 and HMIT1) are structurally atypical members of the GLUT family, which are poorly defined at present, indeed GLUT6 may only be a pseudo-gene .

The confirmed isoforms are expressed in a tissue and cell-specific manner, and exhibit distinct kinetic and regulatory properties, presumably reflecting their specific functional roles. They belong to a much larger 'major facilitator superfamily' of 12 TM transporters that are involved in the transport of a variety of hexoses and other carbon compounds, and include: bacterial sugar-proton symporters (H
+
/xylose and H
+
/arabinose); bacterial transporters of carboxylic acids and antibiotics; and sugar transporters in various yeast, protozoa and higher plants. Nevertheless, amino acid identity within the superfamily may be as low as ~25% . Besides the 12 presumed TM domains, the most characteristic structural feature of the superfamily is a five residue motif (RXGRR, where X is any amino acid). In the GLUT transporters, this motif is present in the presumed cytoplasmic loops connecting TM domains 2 with 3, and also 8 with 9. The 12 TM transporter superfamily appears to be structurally unrelated to the Na
+
-coupled, Na
+
/glucose co-transporters (SGLT1-3) found in the intestine and kidney, which are able to transport glucose against its concentration gradient .

Comparison of the hydropathy profiles for GLUT1-5 reveals that they are virtually superimposable, despite the fact that their primary structures may differ by up to 60%. Of the presumed TM domains, the fourth, fifth and sixth are the most highly conserved, and conserved residues are also found in the short exofacial loops joining the putative TM regions. The presumed cytoplasmic N-and C-termini, and the extracellular loop between the first and second TM domains, show the greatest divergence, both in terms of primary structure and size.

GLUT4 is thought to be an insulin-responsive glucose transporter, expressed in the membranes of the cells and organelles of skeletal muscle, heart and fat. These tissues are insulin-sensitive and respond to increased blood insulin levels by a rapid and reversible 20-30 fold increase in glucose transport. This is thought to be brought about (at least partially) by the translocation of a latent pool of glucose transporters from an intracellular site to the plasma membrane. On entry into the endosomal system, GLUT4 is selectively retained at the expense of other recycling transport that constitutively moves between the endosomes and the cell surface. This retention mechanism might predispose GLUT4 for sorting into transport vesicles that bud slowly from the endosome and that are targeted to the trans-Golgi network (TGN). GLUT4 is sorted into a secretory pathway in the TGN. This probably involves a specialised population of secretory vesicles that excludes other secretory cargo, and that does not fuse constitutively with the plasma membrane. In the absence of insulin, GLUT4 storage vesicles might slowly fuse with endosomes, thereby accounting for the presence of a significant but small pool of GLUT4 in endosomes, even in the absence of insulin. Insulin would then shift GLUT4 from this TGN-endosome cycle to a pathway that takes GLUT4 directly to the cell surface .