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      Molecular Characteristics of Phosphate Transporters and Their Regulation


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          A key process in overall P<sub>i</sub>-homeostasis is renal proximal tubular reabsorption of inorganic phosphate (P<sub>i</sub>), which involves secondary active sodium/phosphate (Na<sup>+</sup>/P<sub>i</sub>) cotransport reabsorption at the brush border membrane. Among the two different molecularly identified Na<sup>+</sup>/P<sub>i</sub> cotransporters, the type-IIa Na<sup>+</sup>/P<sub>i</sub> cotransporter (NaPi-IIa) accounts for up to 70% of brush border membrane transport. Regulation of renal P<sub>i</sub> reabsorption centers around brush border membrane insertion and retrieval of transporter protein under the influence of hormonal and nonhormonal factors. Immunohistochemical and fluorescence techniques have provided new insights into the tissue distribution and the regulation processes. The intrinsic electrogenicity of NaPi-IIa, has allowed detailed studies of the transport kinetics of NaPi-IIa and, combined with mutagenesis methods, structure-function information at the protein level is emerging.

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          Most cited references22

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          Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities.

          Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi) cotransporter that is expressed in the proximal tubule where the bulk of filtered Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of Pi homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal Pi reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi homeostasis and necessary for normal skeletal development.
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            Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine.

            An isoform of the mammalian renal type II Na/Pi-cotransporter is described. Homology of this isoform to described mammalian and nonmammalian type II cotransporters is between 57 and 75%. Based on major diversities at the C terminus, the new isoform is designed as type IIb Na/Pi-cotransporter. Na/Pi-cotransport mediated by the type IIb cotransporter was studied in oocytes of Xenopus laevis. The results indicate that type IIb Na/Pi-cotransport is electrogenic and in contrast to the renal type II isoform of opposite pH dependence. Expression of type IIb mRNA was detected in various tissues, including small intestine. The type IIb protein was detected as a 108-kDa protein by Western blots using isolated small intestinal brush border membranes and by immunohistochemistry was localized at the luminal membrane of mouse enterocytes. Expression of the type IIb protein in the brush borders of enterocytes and transport characteristics suggest that the described type IIb Na/Pi-cotransporter represents a candidate for small intestinal apical Na/Pi-cotransport.
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              Conformational changes couple Na+ and glucose transport.

              The mechanism by which cotransport proteins couple their substrates across cell membranes is not known. A commonly proposed model is that cotransport results from ligand-induced conformational transitions that change the accessibility of ligand-binding sites from one side of the membrane to the other. To test this model, we have measured the accessibility of covalent probes to a cysteine residue (Q457C) placed in the putative sugar-translocation domain of the Na+/glucose cotransporter (SGLT1). The mutant protein Q457C was able to transport sugar, but transport was abolished after alkylation by methanethiosulfonate reagents. Alkylation blocked sugar translocation but not sugar binding. Accessibility of Q457C to alkylating reagents required external Na+ and was blocked by external sugar and phlorizin. The voltage dependence of accessibility was directly correlated with the presteady-state charge movement of SGLT1. Voltage-jump experiments with rhodamine-6-maleimide-labeled Q457C showed that the time course and level of changes in fluorescence closely followed the presteady-state charge movement. We conclude that conformational changes are responsible for the coupling of Na+ and sugar transport and that Q457 plays a critical role in sugar translocation by SGLT1.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                December 2000
                15 September 2000
                : 8
                : 6
                : 366-375
                Institute of Physiology, University of Zurich, Switzerland
                20691 Exp Nephrol 2000;8:366–375
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 81, Pages: 10
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20691
                Self URI (text/html): https://www.karger.com/Article/FullText/20691
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology

                Cardiovascular Medicine,Nephrology
                Protein trafficking,Parathyroid hormone,Pi transport,Proximal tubule


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