Na+-dependent Glucose Cotransporter

The dehydration of cholera is often treated with an oral rehydration solution containing Na+, K+, and glucose or a diet of rice (which contains glucose and amino acids). Glucose is absorbed from the intestinal lumen via the Na+-dependent glucose cotransporters, which cotransport Na into the cells together with glucose. Many amino acids are also absorbed by Na+-dependent cotransport. With the return of Na+ to the cytoplasm, water efflux from the cell into the intestinal lumen decreases. 

Vemaleken A, Veyhl M, Gorboulev V, Kottra G Palm D, Burckhardt BC, Burckhardt G Pipkom R, Beier N, van Amsterdam C, Koepsell H. (2007) Tripeptides of RSI (RSClAl) inhibit a monosaccharide-dependent exocy-totic pathway of Na -D-glucose cotransporter SGLTl with high affinity. 

The incorporation of purified Na /D-glucose cotransporter into the BLM formed by the monolayer folding method was achieved either by fusion of its proteo-liposomes or by folding the lipid layer containing the proteoliposomes. The experimental setup for measuring the currents is the same as in Figure 25. The concentration dependence of the observed currents is shown in Figure 31. A Na ... 

Na+-dependent glucose transporters have now been cloned and sequenced from rabbit kidney (Coady et al., 1990), human intestine (Hediger et al., 1989), and LLC-PKi cells (Ohta et al., 1990) and these transporters show 100%, 85%, and 84% identity with the rabbit intestinal carrier (Wright et al., 1992). In addition, Na+-coupled nucleoside (Pajor and Wright, 1992) and amino acid cotransporters (Kong et al., 1993) have been cloned from rabbit kidney and LLC-PKi cells. The amino acid sequence of the cloned nucleoside transporter shows 61% identity and 80% similarity to the Na+-glucose cotransporter sequence. 

Na -dependent glucose transporters, which are located on the luminal side of the absorptive cells, enable these cells to concentrate glucose from the intestinal lumen. A low intracellular Na concentration is maintained by a Na, K -ATPase on the serosal (blood) side of the cell that uses the energy from ATP cleavage to pump Na out of the cell into the blood. Thus, the transport of glucose from a low concentration in the lumen to a high concentration in the cell is promoted by the cotransport of Na from a high concentration in the lumen to a low concentration in the cell (secondary active transport). 

Ion-dependent solute transport processes such as Na+-glucose and Na+-amino acid cotransporters can be identified in epithelial tissues by observing an elevation in /sc following solute addition in Na+-containing but not Na+-free... 

Transport of many compounds including drugs across cell membranes is mediated by membrane proteins called carrier proteins or channel proteins. Some of these proteins transport only one substrate molecule at a time across the membrane (uniport systems), while others act as cotransport systems (Figure 9.4). Depending on the direction of the second substrate, the proteins are also called symporters or antiporters, for example, Na /glucose cotransporter, H " /peptide cotransporter, or Na /K antiporter (—Na /K -ATPase). 

Fig. 27.12. Na -dependent and facilitative transporters in the intestinal epithelial cells. Both glucose and fructose are transported by the facilitated glucose transpxrrters on the luminal and serosal sides of the absorptive cells. Glucose and galactose are transported by the Na -glucose cotransporters on the luminal (mucosal) side of the absorptive cells.

Amino acids that enter the blood are transported across cell membranes of the various tissues principally by Na -dependent cotransporters and, to a lesser extent, by facilitated transporters (Table 37.1). In this respect, amino acid transport differs from glucose transport, which is Na -dependent transport in the intestinal and renal epithelium but facilitated transport in other cell types. The Na dependence of amino acid transport in liver, muscle, and other tissues allows these cells to concentrate amino acids from the blood. These transport proteins have a different genetic basis, amino acid composition, and somewhat different specificity than those in the luminal membrane of intestinal epithelia. They also differ somewhat between tissues. For instance, the N system for glntamine nptake is present in the liver bnt either not present in other tissues or present as an isoform with different properties. There is also some overlap in specificity of the transport proteins, with most amino acids being transported by more than one carrier. 

Transport systems can be described in a functional sense according to the number of molecules moved and the direction of movement (Figure 41-10) or according to whether movement is toward or away from equilibrium. A uniport system moves one type of molecule bidirectionally. In cotransport systems, the transfer of one solute depends upon the stoichiometric simultaneous or sequential transfer of another solute. A symport moves these solutes in the same direction. Examples are the proton-sugar transporter in bacteria and the Na+ -sugar transporters (for glucose and certain other sugars) and Na -amino acid transporters in mammalian cells. Antiport systems move two molecules in opposite directions (eg, Na in and Ca out). 

Foscarnet competitively inhibits Na -Pj cotransport in animal and human kidney proximal tubule brush border membrane vesicles, reversibly inhibiting sodium-dependent phosphate transport [48, 49]. Renal cortical Na-K-ATPase and alkaline phosphatase activity are not inhibited by foscarnet, nor is proline, glucose, succinate, or Na" transport [48,49]. Foscarnet induces isolated phosphaturia without hypophosphatemia in thyroparathyroidectomized rats maintained on a low phosphorus diet, without affecting glomerular filtration rate, urinary adenosine 3 5 -cyclic monophosphate (cAMP) activity, or urinary calcium, sodium or potassium excretion [48,50]. Sodium-Pj cotransport in brush border membrane vesicles from human renal cortex was reported to be even more sensitive to inhibition by foscarnet than in rat renal brush border membrane vesicles [49]. 

While the characteristics of this type of transport have been studied and identified in a number of cell systems and for a number of substances (Table 6), little is known of the molecular mechanism involved, although kinetic analysis of facilitated diffusion may be found (Stein, 1967 Neame and Richards, 1972). However, because the proposed mechanism involves a reversible reaction of the substrate with a membrane carrier to form a complex which traverses the membrane and releases the substrate at the other side, it may be that facilitated diffusion mechanisms do not differ from those involved in active transport of the same molecule (Csaky, 1965 Wilbrandt, 1972). Specifically, the active transport of D-glucose may simply require the presence and cotransport of sodium ions (Crane, 1962 Stein, 1967). This theory has recently received support from studies of Na+-gradient-dependent uptake of o-glucose by isolated intestinal and renal brush border membranes (Murer and Hopfer, 1974 Kinne et al., 1975). However, the elec-trogenic nature of D-glucose transport is probably more accurately class-... 

---