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Pflugers Arch 2024 Mar 20; doi: 10.1007/s00424-024-02941-0.
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XPR1: a regulator of cellular phosphate homeostasis rather than a Pi exporter.

Burns D , Berlinguer-Palmini R , Werner A .

Phosphate (Pi) is an essential nutrient, and its plasma levels are under tight hormonal control. Uphill transport of Pi into cells is mediated by the two Na-dependent Pi transporter families SLC34 and SLC20. The molecular identity of a potential Pi export pathway is controversial, though XPR1 has recently been suggested by Giovannini and coworkers to mediate Pi export. We expressed XPR1 in Xenopus oocytes to determine its functional characteristics. Xenopus isoforms of proteins were used to avoid species incompatibility. Protein tagging confirmed the localization of XPR1 at the plasma membrane. Efflux experiments, however, failed to detect translocation of Pi attributable to XPR1. We tested various counter ions and export medium compositions (pH, plasma) as well as potential protein co-factors that could stimulate the activity of XPR1, though without success. Expression of truncated XPR1 constructs and individual domains of XPR1 (SPX, transmembrane core, C-terminus) demonstrated downregulation of the uptake of Pi mediated by the C-terminal domain of XPR1. Tethering the C-terminus to the transmembrane core changed the kinetics of the inhibition and the presence of the SPX domain blunted the inhibitory effect. Our observations suggest a regulatory role of XPR1 in cellular Pi handling rather than a function as Pi exporter. Accordingly, XPR1 senses intracellular Pi levels via its SPX domain and downregulates cellular Pi uptake via the C-terminal domain. The molecular identity of a potential Pi export protein remains therefore elusive.

PubMed ID: 38507112
PMC ID: PMC11033234
Article link: Pflugers Arch
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ip6k1 ip6k2 kidins220 kirrel1 myorg ppip5k1 ppip5k2 sf3b4 slc26a1 slc29a3 slc37a3 slc37a4 xpr1
GO keywords: regulation of phosphate transport

Disease Ontology terms: Fanconi syndrome

Article Images: [+] show captions