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Mechanisms of phosphate transport

Nature Reviews Nephrology volume 15, pages 482–500 (2019)Cite this article

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Abstract

Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.

Key points

  • In the past 25 years, the cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the Na+-dependent inorganic phosphate (Pi) cotransporters NaPi-IIa, NaPi-IIb and NaPi-IIc, respectively, has enabled study of the molecular mechanisms that underlie the regulation of renal and intestinal Pi transport.

  • Dietary factors, particularly dietary Pi, as well as hormones and phosphatonins, including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), regulate the expression and activity of the Pi transporters through transcriptional, translational and post-translational mechanisms that involve interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking via endocytosis or exocytosis.

  • Mutations in any of the three transporters can cause dysregulation of epithelial Pi transport, can affect serum Pi levels and can cause damage of various target organs in both humans and rodents, highlighting the importance of these transporters in the maintenance of local and systemic Pi homeostasis.

  • Functional studies together with structure–function studies have provided insights into the transport mechanisms of the NaPi-II cotransporter.

  • The development of small molecules that modify the activity of Pi transporters holds promise for the maintenance of Pi homeostasis in patients with chronic kidney disease and other disorders associated with hyperphosphataemia and its severe cardiovascular and skeletal consequences.

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Fig. 1: PTH-induced internalization of NaPi-IIa and NaPi-IIc.
Fig. 2: Interaction of PDZ proteins with NaPi-IIa and NaPi-IIc in renal proximal tubule cells.
Fig. 3: The effect of membrane lipid composition on the regulation of NaPi-IIa dynamics.
Fig. 4: A kinetic scheme for Na+-coupled Pi transport mediated by NaPi-II cotransporters.
Fig. 5: The molecular structure of NaPi proteins.
Fig. 6: Inhibitors of NaPi-II transporters.

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Acknowledgements

The authors thank X. Wang and K. Myakala, Georgetown University, for help formatting the references.

Reviewer information

Nature Reviews Nephrology thanks M. Ketteler, E. Lederer and H. Segawa, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA

    Moshe Levi

  2. Department of Biomedical Engineering, Laboratory for Fluorescence Dynamics, University of California–Irvine, Irvine, CA, USA

    Enrico Gratton

  3. Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia

    Ian C. Forster

  4. Institute of Physiology, University of Zurich, Zurich, Switzerland, and Swiss National Centres of Competence in Research, NCCR Kidney.CH, Zurich, Switzerland

    Nati Hernando, Carsten A. Wagner, Juerg Biber & Heini Murer

  5. Laboratory of Molecular Toxicology, Department of Toxicology, University of Zaragoza, Zaragoza, Spain

    Victor Sorribas

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  1. Moshe Levi
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  3. Ian C. Forster
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Glossary

Micropuncture

A technique that uses one or more microelectrodes inserted into the glomerulus, renal vessels or specific nephron segments of the kidney in situ to measure glomerular filtration, blood flow or tubular transport processes.

Brush-border membrane vesicles

(BBMVs). Sealed vesicles derived from the brush-border membrane of epithelial cells that are frequently used to study the apical transport of solutes across the apical membrane in vitro. They are obtained upon homogenization of the tissue and precipitation of basolateral membranes with MgCl2.

Lysosomes

Intracellular acidic organelles that contain enzymes that are able to hydrolyse protein, sugars, lipids, RNA and DNA. These enzymes have an acidic optimal pH. Among other substrates, they digest endocytosed material.

Microtubule

A component of the cytoskeleton consisting of polymers of tubulin. They are involved in several cellular processes, including intracellular transport of cargo vesicles to and from the plasma membrane using kinesin or dynein as motor proteins.

Subapical endocytic apparatus

(SEA). A subapical domain of epithelial cells consisting of clathrin-coated pits, endocytic vesicles and membrane-limited tubules called dense apical tubules. These tubules have been proposed to contribute to the sorting and recycling of endocytic cargo and receptors.

Total internal reflection fluorescence (TIRF) microscopy

A technique whereby total internal reflection of the excitation light limits fluorescence detection to approximately 100 nm above the glass or the apical membrane.

Modulation tracking

An orbital tracking method for single particle tracking based on active feedback, which moves microvilli to maintain them within the centre of a scanned pattern.

Raster image correlation spectroscopy

(RICS). A non-invasive technique that detects and quantifies events in a live cell, including the concentration of molecules and diffusion coefficients of molecules.

Number and brightness (N&B) analysis

A technique based on moment analysis for measuring the average number of molecules and brightness in each pixel in fluorescence microscopy images.

Autosomal dominant hypophosphataemic rickets

(ADHR). A rare hereditary disease that has an autosomal dominant mode of inheritance and variable age of onset and is caused by mutations that increase the half-life of FGF23. It is characterized by renal phosphate wasting, hypophosphataemia and inappropriately normal levels of 1,25-dihydroxy-vitamin D3, with patients suffering from bone pain and rickets.

Tumour-induced osteomalacia

Also known as oncogenic hypophosphataemic osteomalacia. A rare syndrome caused by small tumours that secrete fibroblast growth factor 23 (FGF23), matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein 4 (sFRP4). It is characterized by hypophosphataemia due to urinary loss of inorganic phosphate, bone pain and fractures and muscle weakness.

Familial tumoural calcinosis

(FTC). Also known as hyperphosphataemic FTC. A rare autosomal hereditary disorder characterized by hyperphosphataemia due to inactivating mutations in the FGF23, GALNT3 or KL genes and by secondary to reduced urinary excretion of inorganic phosphate, normal or elevated 1,25-dihydroxy-vitamin D3 and ectopic calcification.

Hypomorphic

A hypomorphic mutation is one that results in reduced activity of the encoded protein.

Osteoglophonic dysplasia

A rare autosomal dominant disease caused by mutations in the fibroblast growth factor receptor 1 (FGFR1). Patients exhibit hypophosphataemia due to hyperphosphaturia and abnormal bone growth that results in severe craniofacial abnormalities, short and bowed legs and arms and dwarfism.

X-Linked hypophosphataemic rickets

(XLH). An X-linked hypophosphataemic disease secondary to renal loss of inorganic phosphate caused by mutations in phosphate-regulating neutral endopeptidase (PHEX). Patients suffer from rickets, bone and/or dental deformities and have short stature.

Autosomal recessive hypophosphataemic rickets

(ARHR1). Similar biochemical and phenotypical features as autosomal dominant hypophosphataemic rickets, but with a recessive mode of inheritance. It is caused by mutations in DMP1 (among others).

Fluorescence lifetime imaging microscopy and Förster resonance energy transfer

(FLIM-FRET). A microscopy system that enables determination of protein–protein interactions within 10 nm or less in live cells on the basis of changing lifetimes of the fluorophores.

Sphingomyelin

A phospholipid enriched in saturated fatty acids that is part of the lipid rafts.

BBM fluidity

A measure of the lipid dynamics of the apical brush-border membrane.

Fluorescence anisotropy of diphenylhexatriene

Measurement of the membrane fluidity. A higher value indicates a less fluid membrane.

Lipid microdomains

Also known as lipid rafts. Regions of the membrane that may be smaller than the 200 nm size of the diffraction barrier and that may be dynamic in nature.

Laurdan fluorescence spectroscopy

Laurdan is a fluorescent molecule that is highly sensitive to water penetration and cholesterol within the membrane lipid bilayer.

Glucosylceramide

A membrane glycosphingolipid that is associated with lipid raft formation.

Multiphoton excitation (MPE) fluorescence microscopy

A nonlinear microscopy system in which the exciting light is provided by a two-photon near-infrared laser.

Scanning fluorescence correlation spectroscopy

(SFCS). A technique that performs multiple fluorescence correlation spectroscopy measurements simultaneously by rapidly directing the excitation laser beam in a uniform (circular) scan across the bilayer of the cell membrane in a repetitive fashion. SFCS provides a quantitative and highly sensitive method to study protein diffusion and protein–membrane interactions.

Sotos syndrome

An inborn syndrome characterized by accelerated body length growth, microcephalus and delayed cognitive and motor development. It is caused by deletions on chromosome 5q35 encompassing the NSD1 gene neighbouring the SLC34A1 gene locus.

Compound heterozygosity

Two different recessive mutations of a particular gene.

Minor allele frequency

The frequency at which the second most common allele occurs in a given population.

Hereditary hypophosphataemic rickets with hypercalciuria

(HHRH). An autosomal recessive form caused by mutations in SLC34A3 and characterized by reduced renal phosphate reabsorption, hypophosphataemia, and rickets. It can be distinguished from other forms of hypophosphataemia by increased serum levels of 1,25-dihydroxy-vitamin D3 resulting in hypercalciuria.

Pulmonary alveolar microlithiasis

(PAM). A chronic, slowly fibrosing lung disease caused and characterized by calcium-phosphate microcrystal depositions in the alveolar space.

Cor pulmonale

Right ventricular enlargement secondary to a lung disorder that causes pulmonary arterial hypertension.

Testicular microlithiasis

An asymptomatic deposition of small crystals in testes. It may be associated with the risk of infertility or testicular cancer, but a causal link has not been established to date.

Electrogenic

A membrane transport process that involves net charge transfer accompanying substrate transport.

Electroneutral

A membrane transport process that involves no net charge transfer accompanying substrate transport.

Capacitive currents

Transient currents induced by changes in membrane potential that result from charging and discharging the membrane capacitance or displacement of mobile charges within the transmembrane electric field.

Voltage clamp fluorometry

(VCF). A technique in which time-resolved changes in fluorescence that reflect changes in the microenvironment of fluorophores linked to engineered cysteine residues at the periphery of the protein are measured. The changes in fluorescence can be interpreted as conformational changes induced by the membrane potential and cation availability.

Secondary topology

The orientation of membrane-spanning segments (for example, α-helices) and other secondary structures (for example, linkers and β-sheets) with respect to the inner and outer faces of the membrane.

Substituted cysteine accessibility (SCAM) technique

A technique used to determine secondary topological features by assessing the effect of linking methanethiosulfonate reagents to novel cysteines substituted at sites predicted to be of functional importance.

Repeat swap strategy

A homology modelling strategy applied to membrane transporters that contain repeat units. These are used as templates to predict alternative conformations not available from the crystal structure of the homologous protein.

K i

The inhibitory constant for competitive inhibitors, which is related to the affinity of the inhibitor for the substrate binding site and is independent of the substrate concentration.

Na+ slippage

An older term used to describe uncoupled Na+ leak current mediated by Na+-coupled transporters in the absence of substrate (for example, inorganic phosphate).

IC50

The half-maximal inhibitory concentration — that is, the concentration of inhibitor that reduces transport (or other quantifiable physiological process) to a half at a specific concentration of the substrate that is being transported.

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Levi, M., Gratton, E., Forster, I.C. et al. Mechanisms of phosphate transport. Nat Rev Nephrol 15, 482–500 (2019). https://doi.org/10.1038/s41581-019-0159-y

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