Use of phosphonocarboxylic acids as inhibitors of sodium-phosphate cotransport

Loghman‐Adham, Mahmoud

doi:10.1016/0306-3623(95)02017-9

Cited by 36 publications

(18 citation statements)

References 61 publications

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“…However, PFA has a higher K i (~0.4-0.6 mM (e.g. (VillaBellosta&Sorribas 2009) ) than K 0.5 P i and displays nephrotoxic effects (Loghman-Adham 1996). These characteristics make it unattractive as a means to limit dietary P i absorption and prevent hyperphosphatemia in cases where kidney function is compromised (Wallin&Ryrfeldt 1995).…”

Section: Inhibitors For Slc34 and Slc20 Proteinsmentioning

confidence: 99%

Phosphate Transport Kinetics and Structure-Function Relationships of SLC34 and SLC20 Proteins

Forster

Hernando

Biber

et al. 2012

Current Topics in Membranes

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Transport of inorganic phosphate (P(i)) is mediated by proteins belonging to two solute carrier families (SLC20 and SLC34). Members of both families transport P(i) using the electrochemical gradient for Na(+). The role of the SLC34 members as essential players in mammalian P(i) homeostasis is well established, whereas that of SLC20 proteins is less well defined. The SLC34 family comprises the following three isoforms that preferentially cotransport divalent P(i) and are expressed in epithelial tissue: the renal NaPi-IIa and NaPi-IIc are responsible for reabsorbing P(i) in the proximal tubule, whereas NaPi-IIb is more ubiquitously expressed, including the small intestine, where it mediates dietary P(i) absorption. The SLC20 family comprises two members (PiT-1, PiT-2) that preferentially cotransport monovalent P(i) and are expressed in epithelial as well as nonepithelial tissue. The transport kinetics of members of both families have been characterized in detail using heterologous expression in Xenopus oocytes. For the electrogenic NaPi-IIa/b, and PiT-1,-2, conventional electrophysiological techniques together with radiotracer methods have been applied, as well as time-resolved fluorometric measurements that allow new insights into local conformational changes of the protein during the cotransport cycle. For the electroneutral NaPi-IIc, conventional tracer uptake and fluorometry have been used to elucidate its transport properties. The 3-D structures of these proteins remain unresolved and structure-function studies have so far concentrated on defining the topology and identifying sites of functional importance. DOI: https://doi.org/10.1016/ B978-0-12-394316-3.00010-7 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-73295 Accepted Version Originally published at: Forster, Ian C; Hernando, Nati; Biber, Jürg; Murer, Heini (2012). Phosphate transport kinetics and structure-function relationships of SLC34 and SLC20 proteins. Current Topics in Membranes, I. OVERVIEWTransport of inorganic phosphate (P i ) is mediated by proteins belonging to 2 solute carrier families (SLC20 and SLC34). Members of both families transport P i using the electrochemical gradient for Na + . Whereas the role of the SLC34 members as essential players in mammalian P i homeostasis is well established, that of SLC20 proteins is less well defined. The SLC34 family comprises the following 3 isoforms that preferentially cotransport divalent P i and are expressed in epithelial tissue: the renal NaPi-IIa and NaPi-IIc are responsible for reabsorbing P i in the proximal tubule, whereas NaPi-IIb is more ubiquitously expressed, including the small intestine, where it mediates dietary P i absorption. The SLC20 family comprises 2 members (PiT-1, PiT-2) that preferentially cotransport monovalent P i and are expressed in epithelial as well as non-epithelial tissue. The transport kinetics of members of both families have been characterized in detail using heterologous expression in Xenop...

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Section: Inhibitors For Slc34 and Slc20 Proteinsmentioning

confidence: 99%

Phosphate Transport Kinetics and Structure-Function Relationships of SLC34 and SLC20 Proteins

Forster

Hernando

Biber

et al. 2012

Current Topics in Membranes

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“…The pH was adjusted to 7.3-7.4 with KOH. Three potential inhibitors of Pi uptake were also tested: (i) an inhibitor of Na + /K + ATPase, ouabain, 5·mmol·l -1 (Lucu and Flik, 1999), to determine dependence of Pi uptake on Na + gradient across the apical membrane; (ii) a known specific inhibitor of mammalian NaPi, phosphonoformic acid (PFA), 5·mmol·l -1 (Loghman-Adham, 1996), to determine involvement of NaPi in Pi uptake; and (iii) an inhibitor of cytochrome c oxidase in the mitochondrial respiratory chain, sodium azide (NaN3), 10·mmol·l -1 (Utoguchi et al, 1999), to determine ATP-dependence of Pi uptake. All the inhibitors were purchased from Sigma-Aldrich Co. (St Louis, MO, USA).…”

Section: Pi Uptake Assaymentioning

confidence: 99%

Contributions of different NaPi cotransporter isoforms to dietary regulation of P transport in the pyloric caeca and intestine of rainbow trout

Sugiura

Ferraris

2004

Journal of Experimental Biology

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SUMMARY The anatomical proximity and embryological relationship of the pyloric caeca (PC) and small intestine of rainbow trout has led to the frequent assumption, on little evidence, that they have the same enzymes and transporters. In trout, the PC is an important absorptive organ for dietary nutrients, but its role in dietary P absorption has not been reported. We found that apical inorganic phosphate (Pi) transport in PC comprises carrier-mediated and diffusive components. Carrier-mediated uptake was energy-and temperature-dependent, competitively inhibited and Na+-independent, and greater than the Na+-dependent intestinal uptake. Pi uptake in PC was pH-sensitive in the presence of Na+. Despite the active Pi transport system in PC, high postprandial luminal Pi concentrations (∼20 mmol l–1)indicate that diffusive uptake represents ∼92% of total Pi uptake in PC of fed fish. The nucleotide sequence of a sodium-phosphate cotransporter(NaPi-II) isoform isolated from PC was ∼8% different from the intestinal NaPi cotransporter. PC-NaPi mRNA was abundant in PC but rare in the intestine,whereas intestinal NaPi mRNA was abundant in the intestine but scarce in PC. Dietary P restriction reduced serum and bone P concentrations, increased intestine-type, but not PC-type, NaPi mRNA in PC, and increased Pi uptake in intestine but not in PC. Intestine-type NaPi expression may be useful for predicting dietary P deficiency.

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“…Sodium phosphate cotransporters (Slc34a2) in mammals and Slc34a2a in fish have been demonstrated to play a significant role in P i uptake in the intestine (12,21,30). We therefore investigated the role of the hagfish Slc34a2-like transporter in P i uptake using a pyrophosphate structural analog and putative Slc34a competitive inhibitor, PFA (25). We also investigated Na ϩ -dependent P i uptake in a Na ϩ -limiting environment, as Slc34a has been demonstrated previously to be a Na ϩ -dependent transporter in trout (2) and other higher vertebrates (11,42).…”

Section: Discussionmentioning

confidence: 99%

“…Because PFA acts as a classical competitive inhibitor at the P i binding site of Slc34a (25), it is possible that 10.0 mmol/l PFA was insufficient to produce considerable inhibition at the P i concentrations tested. Unfortunately, the limited solubility of PFA in our salines precluded the use of higher concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…To test for an inhibitory effect of phosphonoformic acid (PFA), PFA was added to Ca 2ϩ -and Mg 2ϩ -free HF saline at a concentration of 10.0 mmol/l. PFA is a structural analog of pyrophosphate and is a known inhibitor of the NaPi-IIb transporter (SLC34A2 in HUGO nomenclature) in mammals (25). Phosphate solutions for concentration-dependent uptake experiments were made by spiking the standard saline with a 100 mmol/l NaH 2PO4 working stock in Ca 2ϩ -and Mg 2ϩ -free HF saline.…”

Section: Methodsmentioning

confidence: 99%

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Phosphate absorption across multiple epithelia in the Pacific hagfish (Eptatretus stoutii)

Schultz

Guffey

Clifford

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Inorganic phosphate (Pi) is an essential nutrient for all organisms, but in seawater, Pi is a limiting nutrient. This study investigated the primary mechanisms of Pi uptake in Pacific hagfish ( Eptatretus stoutii) using ex vivo physiological and molecular techniques. Hagfish were observed to have the capacity to absorb Pi from the environment into at least three epithelial surfaces: the intestine, skin, and gill. Pi uptake in all tissues was concentration dependent, and saturable Pi transport was observed in the skin and gill at <2.0 mmol/l Pi. Gill and intestinal Pi uptake was sodium dependent, but Pi uptake into the skin increased under low sodium conditions. Gill Pi transport exhibited an apparent affinity constant ∼0.23–0.6 mmol/l Pi. A complete sequence of a type II sodium phosphate cotransporter (Slc34a) was obtained from the hagfish gill. Phylogenetic analysis of the hagfish Slc34a transporter indicates that it is earlier diverging than, and/or ancestral to, the other identified vertebrate Slc34a transporters (Slc34a1, Slc34a2, and Slc34a3). With the use of RT-PCR, the hagfish Slc34a transcript was detected in the intestine, skin, gill, and kidney, suggesting that this may be the transporter involved in Pi uptake into multiple epithelia in the hagfish. This is the first measurement of Pi uptake across the gill or skin of any vertebrate animal and first sodium phosphate cotransporter identified in hagfish.

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Use of phosphonocarboxylic acids as inhibitors of sodium-phosphate cotransport

Cited by 36 publications

References 61 publications

Phosphate Transport Kinetics and Structure-Function Relationships of SLC34 and SLC20 Proteins

Phosphate Transport Kinetics and Structure-Function Relationships of SLC34 and SLC20 Proteins

Contributions of different NaPi cotransporter isoforms to dietary regulation of P transport in the pyloric caeca and intestine of rainbow trout

Phosphate absorption across multiple epithelia in the Pacific hagfish (Eptatretus stoutii)

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