Molecular Characteristics of Phosphate Transporters and Their Regulation

Hernando, Nati; Forster, Ian C.; Biber, Jürg; Murer, Heini

doi:10.1159/000020691

Cited by 18 publications

(25 citation statements)

References 72 publications

(85 reference statements)

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“…As a similar regulatory behavior was observed for the intrinsic (NaPi-4) and transfected (NaPi-2) transporter (10,11,14,19), OK cells represent an ideal in vitro system to study molecular determinants responsible for PTH-induced downregulation of the type IIa NaPi cotransporter.…”

Section: Resultsmentioning

confidence: 56%

“…The maximal effect induced by 3-34 PTH is about 50% of that induced by 1-34 PTH (16-18). Also, transiently transfected EGFP-coupled rat type IIa is internalized upon treatment of OK cells with 1-34 PTH (14). Fig.…”

Section: Expression Of the Chimeric And Mutated Cotransporters In Ok mentioning

confidence: 91%

“…Type II NaPi cotransporters contain also such motifs; however, removal of all di-leucine or tyrosine motifs present in rat type IIa did not prevent the PTH internalization of this cotransporter (14), suggesting alternative mediating signals (motifs). The identified K 503 R 504 (or RR for NaPi-4; ref.…”

Section: K503r504 Residues Arementioning

confidence: 98%

“…PTH exerts its effect by an inhibition of proximal tubular brush-border NaPi cotransport associated with a membrane retrieval and lysosomal degradation of type IIa NaPi cotransporters (4,(6)(7)(8)(9). These PTH-induced regulations are retained in cultured opossum kidney (OK) cells for both the endogenous (NaPi-4) and the transfected rat (NaPi-2) type IIa NaPi cotransporter (10)(11)(12)(13)(14). In proximal tubules and in OK cells, two signaling pathways are involved in PTH-induced downregulation of P i transport and of type IIa NaPi cotransporter: protein kinase A and protein kinase C (15)(16)(17)(18)(19).…”

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confidence: 99%

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A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter

Karim

Hernando

Biber

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Type II NaPi cotransporters are expressed in the apical membrane of Pi-(re)absorbing epithelia: the type IIa in renal proximal tubule and the type IIb in small intestine. Parathyroid hormone (PTH) leads to a retrieval from the apical membrane of the type IIa NaPi cotransporter. The type IIa cotransporter is also expressed in opossum kidney (OK) cells, and its expression is under the control of PTH. In the present study, we identified the molecular ''domains'' involved in the PTH-induced retrieval of the type IIa NaPi cotransporter. Wild-type mouse type IIa (mIIa) and type IIb (mIIb) as well as several mIIa-mIIb chimeras and site-directed mutants were fused to the enhanced green fluorescent protein and transfected into OK cells. We found that mIIa but not mIIb was internalized and degraded after incubation with 1-34 (or 3-34) PTH. Using chimeras, we found that the N and C termini were not required in this effect, whereas a ''domain'' located between residues 216 and 658 seemed to be necessary. This region contains two putative intracellular loops with highly conserved sequences between mIIa and mIIb; in the last intracellular loop, two charged amino acids of type IIa (K 503R504) are replaced by uncharged residues in type IIb (N520I521). We generated two mutants in which these residues were interchanged: mIIaNI and mIIbKR. Similarly to mIIa, the mIIbKR mutant was endocytosed in response to 1-34 PTH; in contrast, mIIaNI behaved as mIIb and was not internalized. In conclusion, a dibasic amino acid motif (K 503R504) located in the last intracellular loop of the type IIa NaPi cotransporter is essential for its PTH-induced retrieval.PTH ͉ endocytosis R egulated P i reabsorption in the renal proximal tubule is an important element in overall P i homeostasis. Its rate is mainly controlled by the amount of type IIa NaPi cotransporters expressed in the brush-border membrane of proximal tubular cells (1-4).Parathyroid hormone (PTH) is the main phosphaturic hormone (5). PTH exerts its effect by an inhibition of proximal tubular brush-border NaPi cotransport associated with a membrane retrieval and lysosomal degradation of type IIa NaPi cotransporters (4, 6-9). These PTH-induced regulations are retained in cultured opossum kidney (OK) cells for both the endogenous (NaPi-4) and the transfected rat (NaPi-2) type IIa NaPi cotransporter (10)(11)(12)(13)(14). In proximal tubules and in OK cells, two signaling pathways are involved in PTH-induced downregulation of P i transport and of type IIa NaPi cotransporter: protein kinase A and protein kinase C (15-19). The mechanisms by which these kinase activities affect the cotransporter are not known.The small intestinal brush-border membrane contains the type IIb NaPi cotransporter, identified in a procedure based on homology to IIa (20). Type IIa and type IIb NaPi cotransporters differ in several properties such as tissue distribution (20-22), pH sensitivity (1, 20, 23), and Na ϩ and P i kinetics (1,20,24). Type IIa and type IIb NaPi cotransporters are differently regulated; the type I...

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Section: Resultsmentioning

confidence: 56%

Section: Expression Of the Chimeric And Mutated Cotransporters In Ok mentioning

confidence: 91%

Section: K503r504 Residues Arementioning

confidence: 98%

mentioning

confidence: 99%

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A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter

Karim

Hernando

Biber

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…In proximal tubules, Pi is reabsorbed at the BBM by Na + -dependent transport systems, the Na/Pi transporters [3,12]. Recently.…”

Section: Introductionmentioning

confidence: 99%

Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter

Segawa

Kawakami

Kaneko

et al. 2003

Pflugers Arch - Eur J Physiol

135

119

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Fibroblast growth factor 23 (FGF23), a phosphaturic factor, is involved in the regulation of renal inorganic phosphate (Pi) reabsorption. Proteolysis-resistant FGF23 mutants expressed in rodents reduce Pi uptake in both intestine and kidney, independent of parathyroid hormone action. In the present study, we investigated whether FGF23 affects dietary regulation of Na(+)-dependent Pi (Na/Pi) cotransport in the rat kidney using wild-type FGF23 and an R179Q mutant, which disrupts a consensus proteolytic cleavage motif. Rats injected with naked human FGF23 DNA (wild-type or R179Q mutant) expressed the human FGF23 transcript in the liver. In those animals, plasma calcium and parathyroid hormone levels were not affected by FGF23 (either wild-type or R179Q mutant). FGF23-R179Q did, however, significantly decrease plasma Pi and renal Na/Pi cotransport activity and also the level of type-IIc Na/Pi cotransporter protein in brush-border membrane vesicles (BBMVs) from normal rat kidney. Western blot and immunohistochemical analyses in rats fed a low-Pi diet showed the levels of types-IIa and -IIc Na/Pi cotransporters to be markedly increased. After injection of FGF23-R179Q DNA into the rats fed a low-Pi diet, the levels of the types-IIa and -IIc transporter proteins were decreased. The FGF23 mutant thus blunts the signalling of Pi deprivation to the renal type-II Na/Pi cotransporter, suggesting that the FGF23 pathway could be involved in the signalling of dietary Pi.

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Pathogenesis and Management of Secondary Hyperparathyroidism

Polu

Singh

Calcium and Phosphate Metabolism Management in Chronic Renal Disease

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Molecular Characteristics of Phosphate Transporters and Their Regulation

Cited by 18 publications

References 72 publications

A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter

A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter

Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter

Pathogenesis and Management of Secondary Hyperparathyroidism

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