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Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 7/2019

01-07-2019 | Original article

Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation

Authors: Toru Fujii, Hiroko Segawa, Ai Hanazaki, Shiori Nishiguchi, Sakura Minoshima, Akiko Ohi, Rieko Tominaga, Sumire Sasaki, Kazuya Tanifuji, Megumi Koike, Yuki Arima, Yuji Shiozaki, Ichiro Kaneko, Mikiko Ito, Sawako Tatsumi, Ken-ichi Miyamoto

Published in: Clinical and Experimental Nephrology | Issue 7/2019

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Abstract

Background

Injection of parathyroid hormone (PTH) rapidly stimulates renal Pi excretion, in part by downregulating NaPi-IIa (Npt2a/SLC34A1) and NaPi-IIc (Npt2c/SLC34A3) transporters. The mechanisms underlying the effects of PTH on NaPi-IIc are not fully elucidated.

Methods

We analyzed the effect of PTH on inorganic phosphate (Pi) reabsorption in Npt2a−/− mice to eliminate the influence of Npt2a on renal Pi reabsorption. In opossum kidney (OK) cells and Xenopus oocytes, we investigated the effect of NaPi-IIc transporter phosphorylation. Studies of mice with mutations of NaPi-IIc protein in which serine and threonine were replaced with either alanine (A), which prevents phosphorylation, or aspartic acid (D), which mimics the charged state of phosphorylated NaPi-IIc, were also performed to evaluate the involvement of phosphorylation in the regulation of transport function.

Results

The Npt2a−/− experiments showed that PTH administration rapidly inactivated NaPi-IIc function in the apical membrane of proximal tubular cells. Analysis of mutant proteins (S71, S138, T151, S174, T583) at putative protein kinase C sites, revealed that S138 markedly suppressed the function and cellular expression of mouse NaPi-IIc in Xenopus oocytes and OK cells. In addition, 138D had a short half-life compared with wild-type protein.

Conclusions

The present study suggests that acute regulation of NaPi-IIc protein by PTH is involved in the inactivation of Na+-dependent Pi cotransporter activity and that phosphorylation of the transporter is involved in the rapid modification.
Appendix
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Literature
1.
Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch. 2014;466(1):139–53.CrossRefPubMed
2.
Tatsumi S, Miyagawa A, Kaneko I, Shiozaki Y, Segawa H, Miyamoto K. Regulation of renal phosphate handling: inter-organ communication in health and disease. J Bone Miner Metab. 2016;34(1):1–10.CrossRefPubMed
3.
Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA. 1998;95(9):5372–7.CrossRefPubMedPubMedCentral
4.
Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet. 2006;78(2):179–92.CrossRefPubMed
5.
Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006;78(2):193–201.CrossRefPubMed
6.
Bergwitz C, Miyamoto KI. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 2019;471(1):149–63.CrossRefPubMed
7.
Keusch I, Traebert M, Lotscher M, Kaissling B, Murer H, Biber J. Parathyroid hormone and dietary phosphate provoke a lysosomal routing of the proximal tubular Na/Pi-cotransporter type II. Kidney Int. 1998;54(4):1224–32.CrossRefPubMed
8.
Biber J, Hernando N, Traebert M, Volkl H, Murer H. Parathyroid hormone-mediated regulation of renal phosphate reabsorption. Nephrol Dial Transplant. 2000;15(Suppl 6):29–30.CrossRefPubMed
9.
Traebert M, Volkl H, Biber J, Murer H, Kaissling B. Luminal and contraluminal action of 1–34 and 3–34 PTH peptides on renal type IIa Na-P(i) cotransporter. Am J Physiol Renal Physiol. 2000;278(5):F792-8.CrossRefPubMed
10.
Gattineni J, Friedman PA. Regulation of hormone-sensitive renal phosphate transport. Vitam Horm. 2015;98:249–306.CrossRefPubMed
11.
Murer H, Biber J. Renal sodium-phosphate cotransport. Curr Opin Nephrol Hypertens. 1994;3(5):504–10.CrossRefPubMed
12.
Hayes G, Busch AE, Lang F, Biber J, Murer H. Protein kinase C consensus sites and the regulation of renal Na/Pi-cotransport (NaPi-2) expressed in XENOPUS laevis oocytes. Pflugers Arch. 1995;430(5):819–24.CrossRefPubMed
13.
Deliot N, Hernando N, Horst-Liu Z, Gisler SM, Capuano P, Wagner CA, et al. Parathyroid hormone treatment induces dissociation of type IIa Na+-P(i) cotransporter-Na+/H+ exchanger regulatory factor-1 complexes. Am J Physiol Cell Physiol. 2005;289(1):C159-67.CrossRefPubMed
14.
Weinman EJ, Cunningham R, Wade JB, Shenolikar S. The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a. J Physiol. 2005;567(Pt 1):27–32.CrossRefPubMedPubMedCentral
15.
Weinman EJ, Biswas RS, Peng G, Shen L, Turner CL, Xiaofei E, et al. Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1. J Clin Invest. 2007;117(11):3412–20.CrossRefPubMedPubMedCentral
16.
Weinman EJ, Steplock D, Zhang Y, Biswas R, Bloch RJ, Shenolikar S. Cooperativity between the phosphorylation of Thr95 and Ser77 of NHERF-1 in the hormonal regulation of renal phosphate transport. J Biol Chem. 2010;285(33):25134–8.CrossRefPubMedPubMedCentral
17.
Lanzano L, Lei T, Okamura K, Giral H, Caldas Y, Masihzadeh O, et al. Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone. Am J Physiol Cell Physiol. 2011;301(4):C850-61.CrossRefPubMed
18.
Gutierrez OM, Smith KT, Barchi-Chung A, Patel NM, Isakova T, Wolf M. (1–34) Parathyroid hormone infusion acutely lowers fibroblast growth factor 23 concentrations in adult volunteers. Clin J Am Soc Nephrol. 2012;7(1):139–45.CrossRefPubMed
19.
Segawa H, Yamanaka S, Onitsuka A, Tomoe Y, Kuwahata M, Ito M, et al. Parathyroid hormone-dependent endocytosis of renal type IIc Na-Pi cotransporter. Am J Physiol Renal Physiol. 2007;292(1):F395–403.CrossRefPubMed
20.
Matsumoto N, Hemmi A, Yamato H, Ohnishi R, Segawa H, Ohno S, et al. Immunohistochemical analyses of parathyroid hormone-dependent downregulation of renal type II Na-Pi cotransporters by cryobiopsy. J Med Invest. 2010;57(1–2):138–45.CrossRefPubMed
21.
Segawa H, Yamanaka S, Ito M, Kuwahata M, Shono M, Yamamoto T, et al. Internalization of renal type IIc Na-Pi cotransporter in response to a high-phosphate diet. Am J Physiol Renal Physiol. 2005;288(3):F587-96.CrossRefPubMed
22.
Segawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am J Physiol Renal Physiol. 2009;297(3):F671-8.CrossRefPubMed
23.
Haito-Sugino S, Ito M, Ohi A, Shiozaki Y, Kangawa N, Nishiyama T, et al. Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. Am J Physiol Cell Physiol. 2012;302(9):C1316-30.CrossRefPubMed
24.
Ito M, Sakurai A, Hayashi K, Ohi A, Kangawa N, Nishiyama T, et al. An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells. Am J Physiol Renal Physiol. 2010;299(1):F243-54.CrossRefPubMed
25.
Ohkido I, Segawa H, Yanagida R, Nakamura M, Miyamoto K. Cloning, gene structure and dietary regulation of the type-IIc Na/Pi cotransporter in the mouse kidney. Pflugers Arch. 2003;446(1):106–15.CrossRefPubMed
26.
Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem. 2002;277(22):19665–72.CrossRefPubMed
27.
Forster IC. The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. Pflugers Arch. 2019;471(1):15–42.CrossRefPubMed
28.
Fenollar-Ferrer C, Forrest LR. Structural models of the NaPi-II sodium-phosphate cotransporters. Pflugers Arch. 2019;471(1):43–52.CrossRefPubMed
29.
Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med. 2013;34(2–3):386–95.CrossRefPubMed
30.
Kohler K, Forster IC, Stange G, Biber J, Murer H. Identification of functionally important sites in the first intracellular loop of the NaPi-IIa cotransporter. Am J Physiol Renal Physiol. 2002;282(4):F687-96.CrossRefPubMed
31.
Picard N, Capuano P, Stange G, Mihailova M, Kaissling B, Murer H, et al. Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters. Pflugers Arch. 2010;460(3):677–87.CrossRefPubMed
32.
Guo J, Song L, Liu M, Segawa H, Miyamoto K, Bringhurst FR, et al. Activation of a non-cAMP/PKA signaling pathway downstream of the PTH/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice. Endocrinology. 2013;154(5):1680–9.CrossRefPubMedPubMedCentral
33.
Nagai S, Okazaki M, Segawa H, Bergwitz C, Dean T, Potts JT Jr, et al. Acute down-regulation of sodium-dependent phosphate transporter NPT2a involves predominantly the cAMP/PKA pathway as revealed by signaling-selective parathyroid hormone analogs. J Biol Chem. 2011;286(2):1618–26.CrossRefPubMed
34.
Jacquillet G, Unwin RJ. Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflugers Arch. 2019;471(1):83–98.CrossRefPubMed
35.
Cunningham R, Biswas R, Brazie M, Steplock D, Shenolikar S, Weinman EJ. Signaling pathways utilized by PTH and dopamine to inhibit phosphate transport in mouse renal proximal tubule cells. Am J Physiol Renal Physiol. 2009;296(2):F355-61.CrossRefPubMed
36.
Moe OW. Acute regulation of proximal tubule apical membrane Na/H exchanger NHE-3: role of phosphorylation, protein trafficking, and regulatory factors. J Am Soc Nephrol. 1999;10(11):2412–25.PubMed
37.
Collazo R, Fan L, Hu MC, Zhao H, Wiederkehr MR, Moe OW. Acute regulation of Na+/H + exchanger NHE3 by parathyroid hormone via NHE3 phosphorylation and dynamin-dependent endocytosis. J Biol Chem. 2000;275(41):31601–8.CrossRefPubMed
Metadata
Title
Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation
Authors
Toru Fujii
Hiroko Segawa
Ai Hanazaki
Shiori Nishiguchi
Sakura Minoshima
Akiko Ohi
Rieko Tominaga
Sumire Sasaki
Kazuya Tanifuji
Megumi Koike
Yuki Arima
Yuji Shiozaki
Ichiro Kaneko
Mikiko Ito
Sawako Tatsumi
Ken-ichi Miyamoto
Publication date
01-07-2019
Publisher
Springer Singapore
Published in
Clinical and Experimental Nephrology / Issue 7/2019
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-019-01725-6

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