The intestine and the kidney are two major organs that have epithelia with the specific function of vectorially transferring hexoses across their cells into the bloodstream. In the intestine, the transporters of the mature enterocytes capture the hexoses from the lumen after breakdown of dietary polysaccharides into simple hexoses, D-glucose, D-galactose, and D-fructose. In the kidney, the cells of the proximal tubule capture the glucose from the glomerular filtrate to return it to the blood. These glucose transporters, localized in the brush border membranes of the epithelial cells, differ from the GLUT 1-5 type and share no sequence homology. They are thus members of quite a different protein family.
Moreover, they transport glucose across the cell membrane by having both hexose and Na + binding sites; thus the name Na+-glucose cotransporters. They couple cellular glucose transfer to the inwardly directed electrochemical gradient of Na +. The low intracellular concentration of Na + ions, maintained by Na+-K+ ATPase or the Na+ pump at the basolateral borders of the cells, powers the uphill transfer of glucose through the agency of the cotransporter. The affinity of the sugar molecule for its cotransporter binding site is greater when the Na+ ions are attached to the transporter than when they are removed. Thus the external binding of Na + and its subsequent intracellular debinding (because of the lower intracellular Na + ion concentration) causes the binding, then release, of glucose, allowing it to be transported uphill against its concentration gradient. It is then transported across the basolateral membranes of the cells of the small intestine and kidney, usually by GLUT 2, but in the S3 segments of straight kidney tubules GLUT 1 is found. In this part of the kidney, GLUT 1 is probably involved both in the transepithelial transfer of glucose and in its uptake from the blood to provide energy from cellular glycolysis.
The low concentration of the cotransporters in cell membranes (0.05-0.7%), their hydrophobic nature, and their sensitivity to proteolysis and denaturation made them nearly impossible to prepare by normal biochemical extraction and purification techniques. The first to be cloned and sequenced, by the technique known as functional expression cloning, was SGLT-1, the form found in the rabbit small intestine ( 40). Amphibian eggs of the toad Xenopus laevis can express almost any RNA that is injected into them and make the corresponding protein. Poly(A)*mRNA isolated from the rabbit small intestinal mucosa and microinjected into Xenopus oocytes stimulated Na+-dependent uptake of the hexose analogue a-methyl glucoside that could be blocked by the plant glycoside phlorizin, a high-affinity competitor for the sugar site of the transporter (15). Phlorizin has no effect on the GLUT 1-5 transporters; they are inhibited by the mold metabolite phloretin, which is the aglycone of phlorizin. Phloretin has no effect on the Na+-glucose transporter but blocks the GLUT 1-5 transporters. The predicted topologic organization of SGLT-1 in the cell membranes was surmised from its amino acids and, like the glucose transporter family, it is a large polypeptide with 12 putative membrane-spanning a-helices ( Fig.. 3,4). The polypeptide is glycosylated at one site, but this has little effect on its function ( 41). Radiation inactivation analysis of SGLT-1 suggests that the functional form in the membrane is a tetramer. Human SGLT-1 cDNA encodes a transporter with 84% amino acid sequence identity to the rabbit SGLT-1. It is composed of 664 amino acids. The gene for human SGLT-1 is located on chromosome 22 at q11.2®qter.
Figure 3.4. Highly schematic diagram illustrating the predicted secondary structure model of the Na +-glucose-cotransporter (SGLT-1) molecule in the cell membrane (solid). The putative membrane-spanning a-helices are shown as rectangles numbered 1-12 connected by linked amino-acid chains (lines). An outer glycosylation site is shown (CHO). It has little effect on carrier function. (Adapted from Wright EM, Turk E, Zabel B, et al. J Clin Invest 1991;88:1435-40.)
More recently, it has been shown that there are three different isoforms of the SGLT cotransporters, designated SGLT-1, SGLT-2 (672 amino acids), and SGLT-3 (16). The cotransporters SGLT-1 and -2 have different glucose-Na + coupling ratios, the former high-affinity cotransporter (K m » 0.8 mmol/L), primarily expressed in the small intestine, transports each glucose molecule with two Na+ ions, while the latter, lower-affinity (Km » 1.6 mmol/L) cotransporter, expressed in the kidney tubules, transports glucose with one Na+. SGLT-3, isolated from pig intestine, is a low-affinity cotransporter. It has approximately 60% homology in amino acid sequence to SGLT-2 (42).
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