Phosphate transporters: a tale of two solute carrier families

Virkki, Leila V.; Biber, J; Murer, Heini; Forster, Ian C.

doi:10.1152/ajprenal.00228.2007

Cited by 215 publications

(246 citation statements)

References 126 publications

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“…1A) that comprises a sequence of partial reactions representing the transitions between unique conformational states of the protein. 37,[41][42][43] Under normal physiological conditions, the cotransport cycle begins in the outward facing conformation of the empty carrier (state 1), which favors ordered binding of two Na + ions, followed by binding of one divalent P i and a 3 rd Na + ion from the external medium. A translocation partial reaction of the fully loaded carrier (transition 4↔5) occurs, followed by release of substrates to the cytosol to leave the carrier in state 8.…”

Section: The Uncoupled Leak Of Slc34 Proteinsmentioning

confidence: 99%

“…They are also expressed in epithelial membranes in the small intestine and other organs (testes, lung, liver), where their physiological function is less well understood (reviewed see ref. 37). The family comprises three isoforms that prefer divalent P i as the driven substrate: NaPi-IIa, NaPi-IIb catalyze electrogenic transport with a Na + :P i stoichiometry of 3:1 and one net charge is translocated per transport cycle; 38,39 NaPi-IIc is electroneutral and therefore cotransports with a Na + :P i stoichiometry of 2:1.…”

Section: The Uncoupled Leak Of Slc34 Proteinsmentioning

confidence: 99%

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The leak mode of type II Na⁺-Pi cotransporters

Andrini¹,

Ghezzi²,

Murer³

et al. 2008

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Na + -coupled phosphate cotransporters of the SLC34 gene family catalyze the movement of inorganic phosphate (P i ) across epithelia by using the free energy of the downhill electrochemical Na + gradient across the luminal membrane. Electrogenic (NaPiIIa/b) and electroneutral (NaPi-IIc) isoforms prefer divalent P i and show strict Na + :P i stoichiometries of 3:1 and 2:1, respectively. For electrogenic cotransport, one charge is translocated per transport cycle. When NaPi-IIa or NaPi-IIb are expressed in Xenopus oocytes, application of the P i transport inhibitor phosphonoformic acid (PFA) blocks a leak current that is not detectable in the electroneutral isoform. In this review, we present the experimental evidence that this transport-independent leak originates from a Na + -dependent uniport carrier mode intrinsic to NaPi-IIa/b isoforms. Our findings, based on the characteristics of the PFA-inhibitable leak measured from wild type and mutant constructs, can be incorporated into an alternating access class model in which the leak and cotransport modes are mutually exclusive and share common kinetic partial reactions. IntroductionSecondary-active cotransporters catalyze uphill solute movement across membranes by using the free energy available from the electrochemical gradient of the driving substrate, usually a monovalent cation (Na + , H + or K + ). The transport cycles of many members of this class are electrogenic, whereby net charge transfer accompanies cotransport and the partial reactions that constitute the transport cycle show voltage dependent kinetics. We can investigate the kinetics of these carriers by electrophysiological techniques, as ideally the substrate-induced current is an indirect measure of the transport rate for a constant number of charges translocated per cycle. Uncoupled currents give rise to deviations from the tightly coupled electrogenicity and strict stoichiometry between driving and driven substrates that is expected of the ideal secondary-active carrier. They are also referred to as leak or slippage currents (reviewed in refs. 1 and 2) and are intimately associated with the heterologous expression of the carrier protein. Their co-existence alongside the coupled transport electrogenic activity has led to a reassessment of the traditional view of channels and carriers as unique molecular entities (reviewed in ref.3).Uncoupled currents are commonly sub-classified as transportdependent and transport-independent currents, depending on whether they are detectable in the absence or presence of substrate. Cotransporters can exhibit one or both types of uncoupled current with different contributing ions. Uncoupled currents appear to be ubiquitous among electrogenic carriers and they have been described for gene products of at least nine solute carrier families identified in the human genome 4 (Table 1). Within a given solute carrier family, the properties of the uncoupled currents can also vary considerably for different isoforms, measured under the same experimental conditions. For examp...

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Section: The Uncoupled Leak Of Slc34 Proteinsmentioning

confidence: 99%

Section: The Uncoupled Leak Of Slc34 Proteinsmentioning

confidence: 99%

The leak mode of type II Na⁺-Pi cotransporters

Andrini¹,

Ghezzi²,

Murer³

et al. 2008

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“…Cellular P i levels are controlled by type III Na + -dependent P i co-transporters (Virkki et al 2007). This SLC20 family of transporters includes PiT-1 (SLC20A1) and PiT-2 (SLC20A2) (Collins et al 2004).…”

Section: The Role Of Transporters In Mv-mediated Initiation Of Skeletmentioning

confidence: 99%

Biophysical aspects of biomineralization

et al. 2017

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During the process of endochondral bone formation, chondrocytes and osteoblasts mineralize their extracellular matrix (ECM) by promoting the synthesis of hydroxyapatite (HA) seed crystals in the sheltered interior of membranelimited matrix vesicles (MVs). Several lipid and proteins present in the membrane of the MVs mediate the interactions of MVs with the ECM and regulate the initial mineral deposition and posterior propagation. Among the proteins of MV membranes, ion transporters control the availability of phosphate and calcium needed for initial HA deposition. Phosphatases (orphan phosphatase 1, ectonucleotide pyrophosphatase/ phosphodiesterase 1 and tissue-nonspecific alkaline phosphatase) play a crucial role in controlling the inorganic pyrophosphate/inorganic phosphate ratio that allows MVmediated initiation of mineralization. The lipidic microenvironment can help in the nucleation process of first crystals and also plays a crucial physiological role in the function of MVassociated enzymes and transporters (type III sodiumdependent phosphate transporters, annexins and Na + /K + ATPase). The whole process is mediated and regulated by the action of several molecules and steps, which make the process complex and highly regulated. Liposomes and proteoliposomes, as models of biological membranes, facilitate the understanding of lipid-protein interactions with emphasis on the properties of physicochemical and biochemical processes. In this review, we discuss the use of proteoliposomes as multiple protein carrier systems intended to mimic the various functions of MVs during the initiation and propagation of mineral growth in the course of biomineralization. We focus on studies applying biophysical tools to characterize the biomimetic models in order to gain an understanding of the importance of lipid-protein and lipid-lipid interfaces throughout the process.Keywords Lipid microenvironment . Biomineralization . Matrix vesicles . Liposome . Proteoliposome . Hydroxyapatite Mineralization process and the biogenesis of matrix vesiclesMineralization of cartilage and bone occurs by a series of physicochemical and biochemical processes that together facilitate the deposition of calcium phosphate. The deposited calcium phosphate is subsequently converted into hydroxyapatite (HA) [Ca 10 (PO 4 ) 6 (OH) 2 ] in specific areas of the extracellular matrix (ECM). Various experiments have revealed the presence of HA crystals both inside and outside collagen fibrils in the ECM (McNally et al. 2012) and also within the

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“…The current lack of a 3-D structure of the mammalian SLC34 proteins or their bacterial homologs, means that structural information is based on indirect biophysical and biochemical studies on wild-type and engineered mutations, e.g. (Forster et al, 2002;Virkki et al, 2007). SLC34 proteins are all assumed to be functional monomers (Kohler et al, 2000), although indirect evidence suggests they may exist as dimers at the BBM Gisler et al, 2007).…”

Section: Structure-function Relationships Of Slc34 Proteinsmentioning

confidence: 99%

“…The gene products of the SLC20 family belong to a unique class of proteins that are represented in all phyla Virkki et al, 2007). Compared with SLC34 proteins, relatively few structure-function studies have been undertaken.…”

Section: Structure-function Relationsmentioning

confidence: 99%

Phosphate transporters of the SLC20 and SLC34 families

Forster

Hernando

Biber

et al. 2013

Molecular Aspects of Medicine

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Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology. AbstractTransport of inorganic phosphate (P i ) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na + -dependent, secondary-active cotransporters to transport P i across cell membranes. The SLC34 proteins are expressed in specific organs important for P i homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in P i reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates P i absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity,regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarises our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiologies and pharmacology.3

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Phosphate transporters: a tale of two solute carrier families

Cited by 215 publications

References 126 publications

The leak mode of type II Na⁺-Pi cotransporters

The leak mode of type II Na⁺-Pi cotransporters

Biophysical aspects of biomineralization

Phosphate transporters of the SLC20 and SLC34 families

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Phosphate transporters: a tale of two solute carrier families

Cited by 215 publications

References 126 publications

The leak mode of type II Na+-Pi cotransporters

The leak mode of type II Na+-Pi cotransporters

Biophysical aspects of biomineralization

Phosphate transporters of the SLC20 and SLC34 families

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The leak mode of type II Na⁺-Pi cotransporters

The leak mode of type II Na⁺-Pi cotransporters