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      The Opossum Kidney Cell Type IIa Na/P i Cotransporter Is a Phosphoprotein

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          Background/Aim: Parathyroid hormone (PTH)-dependent inhibition of proximal tubular P<sub>i</sub> reabsorption is mediated by protein kinase A and/or C and is associated with reduced border membrane expression of the type IIa Na/P<sub>i</sub> cotransporter. The aim of this study was to analyze phosphorylation of the type IIa cotransporter protein. Methods: Opossum kidney cells were used as a ‘proximal tubular’ cell model. Protein phosphorylation was determined by immunoprecipitation of the type IIa Na/P<sub>i</sub> cotransporter, followed by autoradiography. The transporter protein content was evaluated by Western blotting and transport activity by tracer P<sub>i</sub> uptake. Results: Under control conditions (no PTH) the transporter was phosphorylated; upon treatment with PTH, a decrease in phosphorylation was observed. A protein phosphatase inhibitor (okadaic acid) was unable to prevent PTH-induced Na/P<sub>i</sub> cotransporter inhibition but reduced transporter degradation. Conclusion: The type IIa Na/P<sub>i</sub> cotransporter is a phosphoprotein, but alterations in its phosphorylation seem not to be involved in P<sub>i</sub> transport inhibition.

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          Most cited references 4

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          Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter.

          We have studied the involvement of proteolytic pathways in the regulation of the Na/Pi cotransporter type II by parathyroid hormone (PTH) in opossum kidney cells. Inhibition of lysosomal degradation (by leupeptin, ammonium chloride, methylamine, chloroquine, L-methionine methyl ester) prevented the PTH-mediated degradation of the transporter, whereas inhibition of the proteasomal pathway (by lactacystin) did not. Moreover it was found (i) that whereas lysosomal inhibitors prevented the PTH-mediated degradation of the transporter they did not prevent the PTH-mediated inhibition of the Na/Pi cotransport and (ii) that treating opossum kidney cells with lysosomal inhibitors led to an increased expression of the transporter without any concomitant increase in the Na/Pi cotransport. Further analysis by subcellular fractionation and morphological techniques showed (i) that the Na/Pi cotransporter is constitutively transported to and degraded within late endosomes/lysosomes and (ii) that PTH leads to the increased degradation of the transporter in late endosomes/lysosomes.
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            Parathyroid hormone and dietary phosphate provoke a lysosomal routing of the proximal tubular Na/Pi-cotransporter type II.

            A decrease of proximal tubular reabsorption of phosphate (Pi), which can be provoked by parathyroid hormone (PTH) or by a high Pi-diet, has been shown to correlate with a decrease of the number of type II Na/Pi-cotransporters residing in the brush border membrane. While both PTH and a high Pi-diet lead to an internalization of type II cotransporters, the further cellular routing of internalized cotransporters has not been established unequivocally. To prevent lysosomal degradation, rats were treated with leupeptin prior to the injection of PTH or feeding acutely with a high Pi-diet. Kidney cortex were recovered and used for immunohistochemistry. In parallel, brush border membranes and lysosomes were isolated and analyzed by Western blotting. Under both conditions (PTH and high Pi-diet), a strong overlap of internalized type II cotransporters with the late endosomes/lysosomes was observed by immunohistochemistry. In agreement, the content of type II Na/Pi-cotransporters was increased in lysosomes isolated from the corresponding tissues. These results suggest that in proximal tubular cells type II Na/Pi-cotransporters internalized due to the action of PTH and acute high Pi-diet are routed to the lysosomes, and likely do not enter a recycling compartment.
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              A molecular view of proximal tubular inorganic phosphate (Pi) reabsorption and of its regulation.

               H Murer,  J Biber (1997)
              In recent years, two mammalian proximal tubular brush border membrane Na/Pi cotransporters (types I and II) have been structurally identified by expression cloning techniques. Oocyte expression studies have shown that only the transport characteristics of the type II transporter correspond to the well-known properties of proximal tubular brush border membrane of Pi transport. In studies on physiological regulation by hormonal and non-hormonal factors a direct involvement and determining role of the type II transporter has been documented. Most interestingly, specific membrane retrieval/insertion phenomena participate in acute (minutes/hours) adjustments of brush border membrane Na/Pi cotransport rates; for chronic (hours/days) alterations also specific resynthesis/degradation processes participate. In pathophysiological alterations (e.g. in X-linked hypophosphataemia and in heavy metal-induced nephrotoxicity) the expression of the type II Na/Pi cotransporters is reduced and explains the observed phosphaturia.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                24 January 2001
                : 24
                : 1
                : 1-4
                Institute of Physiology, University of Zurich, Zurich, Switzerland
                54198 Kidney Blood Press Res 2001;24:1–4
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 14, Pages: 4
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/54198
                Original Paper

                Cardiovascular Medicine, Nephrology

                Phosphorylation, Type IIa Na/Pi Cotransporter, Phosphoprotein


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