Physiological Regulation of Renal Sodium-Dependent Phosphate Cotransporters

Pflugers Arch - Eur J Physiol

Hernando

Forster

et al. 2008

167

154

Homeostasis of inorganic phosphate (P i ) is primarily an affair of the kidneys. Reabsorption of the bulk of filtered P i occurs along the renal proximal tubule and is initiated by apically localized Na + -dependent P i cotransporters. Tubular P i reabsorption and therefore renal excretion of P i is controlled by a number of hormones, including phosphatonins, and metabolic factors. In most cases, regulation of P i reabsorption is achieved by changing the apical abundance of Na + /Pi cotransporters. The regulatory mechanisms involve various signaling pathways and a number of proteins that interact with Na + /P i cotransporters.

“…The phosphaturic effect observed at elevated serum levels of FGF-23 correlated with a decrease of the abundance of NaPi-lla and NaPi-llc [79,80]. Moreover, FGF23…”

Section: Phosphatoninsmentioning

confidence: 92%

Regulation of phosphate transport in proximal tubules

Pflugers Arch - Eur J Physiol

Hernando

Forster

et al. 2008

167

154

“…Renal regulation of NaPi-IIa has been the subject of extensive reviews (Murer, Hernando et al 2000;Werner&Kinne 2001;Tenenhouse&Murer 2003;Miyamoto, Segawa et al 2004;Tenenhouse 2005;Forster, Hernando et al 2006). The regulation of P i reabsorption centers on controlling the number of transporter proteins in the proximal tubule brush border membrane.…”

Section: Fig 1 Near Herementioning

confidence: 99%

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

Forster

Hernando

Current Topics in Membranes

et al. 2012

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...

“…Consistent with electroneutral cotransport of divalent P i , it has been proposed that NaPi-IIc cotransports with a 2:1 Na ϩ ͞HPO 4 2Ϫ stoichiometry (2,10). It follows that NaPi-IIc may lack one of the three Na ϩ binding sites postulated for NaPi-IIa.…”

mentioning

confidence: 93%

“…Two isoforms of type II Na ϩ -coupled P i cotransporters (NaPi-II), both localized at the proximal tubule apical brush border membrane, have been identified. Both cotransporters mediate inward transport of P i by using the inwardly directed Na ϩ gradient (1,2). Type IIa cotransporters (SLC34A1 or NaPi-IIa) couple three Na ϩ ions to the cotransport of one divalent P i ion, and each transport cycle is accompanied by the inward translocation of one net positive charge (3,4).…”

mentioning

confidence: 99%

Renouncing electroneutrality is not free of charge: Switching on electrogenicity in a Na ⁺ -coupled phosphate cotransporter

Bacconi

Virkki

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

et al. 2005

104

Renal type IIa Na ؉ -coupled inorganic phosphate (Pi) cotransporters (NaPi-IIa) mediate divalent P i transport in an electrogenic manner, whereas the renal type IIc isoform (NaPi-IIc) is electroneutral, yet it shows high sequence identity with NaPi-IIa. Dual uptake ( 32 Pi͞ 22 Na) assays confirmed that NaPi-IIc displayed Na ؉ -coupled Pi cotransport with a 2:1 (Na ؉ :Pi) stoichiometry compared with 3:1 established for NaPi-IIa. This finding suggested that the electrogenicity of NaPi-IIa arises from the interaction of an additional Na ؉ ion compared with NaPi-IIc. To identify the molecular elements responsible for the functional difference between isoforms, we used chimera and amino acid replacement approaches. Transport activity of chimeras constructed with NaPi-IIa and NaPi-IIc indicated that residues within the first six transmembrane domains were essential for the electrogenicity of NaPi-IIa. Sequence comparison between electrogenic and electroneutral isoforms revealed differences in the charge and polarity of residues clustered in three areas, one of which included part of the predicted third transmembrane domain. Here, substitution of three residues with their NaPi-IIa equivalents in NaPi-IIc (S189A, S191A, and G195D) resulted in a transporter that displayed a 1:1 charge͞P i coupling, a 3:1 Na ؉ :Pi stoichiometry, and transient currents that resembled pre-steadystate relaxations. The mutant's weaker voltage dependency and 10-fold lower apparent P i affinity compared with NaPi-IIa indicated that other residues important for the NaPi-IIa kinetic fingerprint exist. Our findings demonstrate that, through a minimal number of side chain substitutions, we can effect a switch from electroneutral to electrogenic cotransporter function, concomitant with the appearance of a cosubstrate interaction site.S econdary-active transporter proteins mediate uphill transport of a solute by tapping into the free energy provided by the concentration gradient of a coupled ion that is specific to the transporter protein (e.g., H ϩ , K ϩ , or Na ϩ ). The coupling between driving and driven species confers a strict stoichiometric ratio on cotransport function. When stoichiometrically coupled movement of net charge accompanies cotransport, an additional driving force is available, derived from the free energy established by the transmembrane electric field. For such electrogenic cotransporters, it follows that membrane voltage also becomes a kinetic determinant of the transport mechanism; moreover, under physiological conditions, it can serve to enhance the concentrating ability of the transport protein.One of the many physiologically important transport processes that rely on a secondary active mechanism is reabsorption of inorganic phosphate (P i ) in the renal proximal tubule. Two isoforms of type II Na ϩ -coupled P i cotransporters (NaPi-II), both localized at the proximal tubule apical brush border membrane, have been identified. Both cotransporters mediate inward transport of P i by using the inwardly directed Na ϩ gradient (1, ...