Cotransporters phosphate

Fig. 11.4. H uman duodenal expression variability of phosphate and ABC transporters (unpublished data). Shaded box indicates 25-75% of expression range, the line within the box marks the median, and error bars indicate 10-90% of expression range. SLC17A4, sodium phosphate cotransporter SLC25A3,...

Kos, C. H., et al. Comparative mapping of Na+-phosphate cotransporter genes, NPT1 and NPT2, in human and rabbit. Cytogenet. Cell. Genet. 

Hartmann, C. M., et al. Structure of murine and human renal type II Na+-phosphate cotransporter genes (Npt2 and NPT2). Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 7409-7414. 

H+ cotransporters of low specificity.500 A Cl- / oxalate transporter is one of several ion exchange proteins in the kidney.501 Transport systems for ADP, phosphate, dicarboxylates, and other anions are very active in mitochondrial membranes (Chapter 18). 

Recently, a second transport system for efflux of Ca2+ from E. coli has been identified.190 This is a calcium-phosphate symporter, which catalyzes a 1 1 cotransport of calcium and phosphate, probably in exchange for protons. 

Ni B, Rosteck PR, Jr., Nadi NS, Paul SM (1994) Cloning and expression of a cDNA encoding a brain-specific Na(+)-dependent inorganic phosphate cotransporter. Proc Natl Acad Sci USA 91 5607-5611. 

Peerce, B.E. (1989). Identification of the intestinal Na-phosphate cotransporter. Am. J. Physiol. 256, G645-G652. 

Peerce, B.E., Cedilote, M., Seifert, S., Levine, R., Kiesling, C., Clarke, R.D. (1993). Reconstitution of intestinal Na+-phosphate cotransporter. Am. J. Physiol. 264, G609-G616. 

It is believed that the major part of inorganic phosphor absorption in the intestine occurs via Na+-dependent phosphate cotransporter NaPi-Iib (SLC34A2, Xu et al. 1999). Small drugs like phosphocarbonic acid and foscamet are transported by this transporter (Swaan et al. 1995 Tsuji and Tamai 1996). However, the substrate range is rather limited including only inorganic phosphate compounds. 

The overall transport reaction, in terms of references species, for the phosphate-hydrogen cotransporter is ... 

X-linked hypophosphatemic rickets is caused by abnormal reabsorption of phosphate in the proximal renal tubule, resulting in excessive excretion of phosphate and hence hypophosphatemia. There may also be blunting of the normal increase in calcidiol 1 -hydroxylase activity in response to hypophosphatemia. The gene responsible for the condition has been identified (the PHEX gene) its product is a membrane-bound endopeptidase that normally acts to clear the hormone phosphatonin from the circulation. Phosphatonin acts to decrease the activity of the sodium/phosphate cotransporter in the kidney (Drezner, 2000). 

Active transport may be subdivided into primary transport/ which is directly coupled to substrate oxidation or high-energy phosphate hydrolysis/ or secondary transport/ which is coupled to cotransport of another molecule or ion down its thermodynamic gradient. We will first consider the thermodynamics of membrane transport and then review the four basic mechanisms. 

About 85% of the body s phosphate occurs in bones, with 14% in soft tissues and about 1.0% in the extracellular fluids. The normal range of phosphate intake is 20 to 50 mmol/day (0-6-1.5 g phosphorus/day). Phosphate is absorbed throughout the small intestines. In the duodenum, it is absorb by an Na-dependent transport mechanism. Here, transport of the phosphate is coupled with die cotransport of a sodium ion. The rate of Na-dependent transport of phosphate is enhanced by 1,25-(0H)2D3, Phosphate transport in the jejunum and ileum occurs by a passive mechanism. The rate of phosphate transport in this case is dependent mainly on the concentration of phosphate in the lumen and is independent of the levels of other nutrients and independent of energy-using processes. About 200 mg of phosphorus is excreted per day in fluids of the gastnointeslinai tract. About two-thirds of this phosphorus is reabsorbed by the gut. 

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]. 

Tenenhouse HS, Gauthier C, Martel J, Gesek FA, Coutermarsh BA, Friedman PA. Na -phosphate cotransport in mouse distal convoluted tubule cells Evidence for Glvr-1 and Ram-1 gene expression. J Bone Miner Res 1998 13 590-7. 

Furthermore, in the apical tubular membrane, the transport proteins Oatpl, Oatkl, and Oatk2, the Na +/phosphate cotransporter NPTl, and the primary active export proteins P-glycoprotein, Mrp2, Mrp4, and Berp have been identified [12, 95, 97-100]. Substrate requirements of the ABC transporters have already been discussed in the context of hepatic transport systems. Renal ABC transporters are well... 

McKenna, C.E., Pham, P.-T.T., Rassier, M.E., and Dousa, T.P., a-Halo [(phenylphosphi-nyl)methyl]phosphonates as specific inhibitors of Na -gradient-dependent Na -phosphate cotransport across renal brush border membrane, J. Med. ( hem., 35, 4885, 1992. 

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