Symporter

The gradients of H, Na, and other cations and anions established by ATPases and other energy sources can be used for secondary active transport of various substrates. The best-understood systems use Na or gradients to transport amino acids and sugars in certain cells. Many of these systems operate as symports, with the ion and the transported amino acid or sugar moving in the same direction (that is, into the cell). In antiport processes, the ion and the other transported species move in opposite directions. (For example, the anion transporter of erythrocytes is an antiport.) Proton symport proteins are used by E. coU and other bacteria to accumulate lactose, arabinose, ribose, and a variety of amino acids. E. coli also possesses Na -symport systems for melibiose as well as for glutamate and other amino acids. 

Elecironeutral symport, has also been formulated as Pp70H antiport... 

Figure 12-11. Combination of phosphate transporter ( ) with the adenine nucleotide transporter ((2)) in ATP synthesis. The H+ZP, symport shown is equivalent to the P /OH antiport shown in Figure 12-10. Four protons are taken into the mitochondrion for each ATP exported. However, one less proton would be taken in when ATP is used inside the mitochondrion.

Figure 12-13. Malate shuttle for transfer of reducing equivalents from the cytosol into the mitochondrion. Ketoglutarate transporter , glutamate/aspartate transporter (note the proton symport with glutamate).

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). 

Figure 41-14. The transcellular movement of glucose in an intestinal cell. Glucose follows Na+ across the luminal epithelial membrane. The Na+ gradient that drives this symport is established by Na+ -K+ exchange, which occurs at the basal membrane facing the extra-ceiiuiarfiuid compartment. Glucose at high concentration within the ceii moves "downhill" into the extracel-iuiarfiuid by fadiitated diffusion (a uniport mechanism).

The galactose, arabinose and xylose transporters of E. coli The bacterium E. coli possesses at least 7 proton-linked, active transport systems for sugars (for a recent review see [212]). Three of these transporters, which catalyze the uptake of L-arabinose, D-xylose and D-galactose by symport with protons, are related in sequence to the sugar transporters discussed above. They probably represent the best-characterized of the non-mammalian transporters, and so are discussed here in some detail. 

In bacteria, accumulation of substrates against a concentration gradient can occur through two main classes of transport systems (see [30] for a summary). The prototype of the first class of transporters is the /3-galactoside permease of Escherichia coli (see [31]). It is a relatively simple system involving only a single membrane-bound protein. It catalyzes a lactose-H symport. Other transporters... 

The transport of toluene-4-sulfonate into Comamonas testosteroni has been examined (Locher et al. 1993), and rapid uptake required growth of the cells with toluene-4-sulfonate or 4-methylbenzoate. From the results of experiments with various inhibitors, it was concluded that a toluenesulfonate anion/proton symport system operates rather than transport driven by a difference in electrical potential (A (/), and uptake could not take place under anaerobic conditions unless an electron acceptor such as nitrate was present. 

The difference in the hydrogen ion electrochemical potential, formed in bacteria similarly as in mitochondria, can be used not only for synthesis of ATP but also for the electrogenic (connected with net charge transfer) symport of sugars and amino acids, for the electroneutral symport of some anions and for the sodium ion/hydrogen ion antiport, which, for example, maintains a low Na+ activity in the cells of the bacterium Escherichia coli. 

While the lactate-H+ symporter and the K+/H+ exchanger are involved in acidification of the cell, the Na+/H+ exchanger present in the basal cells exports protons out of the cell in exchange for Na+ [139]. It was observed that removal of Na+ from the Ringer s solution decreased intracellular pH by 0.5 unit in basal cells, possibly due to inhibition of the Na+/H+ exchanger. As the basal cells are the precursors for the superficial cells of the corneal epithelium, it is quite likely that similar exchange processes are also present in the superficial layer, the principal barrier to ion and drug transport [99,103],... 

Na+, K+, 2C1 symporter mechanism ascending limb of the Loop of Henle... 

Thiazide diuretics such as chlorothiazide act on the distal tubule, a portion of the tubule that is permeable to sodium. The mechanism of action of these diuretics involves inhibition of NaCl reabsorption by blocking the Na+, CL symporter in the luminal membrane. The thiazide diuretics are only moderately effective due to the location of their site of action. Approximately 90% of the filtered Na+ ions have already been reabsorbed when the filtrate reaches the distal tubule. These drugs may be used for treatment of edema associated with heart, liver, and renal disease. Thiazide diuretics are also widely used for the treatment of hypertension. 

G. Fischer et al. Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter., Eur. J. 

Daniel, H. Function and molecular structure of brush border membrane peptide/H+ symporters. J. Membr. 

Bretschneider, B., M. Brandsch, and R. Neubert. Intestinal transport of beta-lactam antibiotics analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux. Pharm. Res. 1999, 16, 55-61. 

Brandsch, M., et al. Evidence for the absolute conformational specificity of the intestinal H+/peptide symporter, PEPT1. /. Biol. Chem. 1998, 273, 3861-3864. 

EGER targeting was also used for systemic delivery of pDNA expressing the sodium iodide symporter (NIS) gene to liver cancer cells, followed by administration of radioactive isotope iodine-131, which accumulates in the tumor by NIS-mediated uptake in radiotherapeutic doses [227]. 

---