ArticleThe Journal of biological chemistry2020
Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 70 citations in OpenAlex.
- Three phosphatase families form a community: The phosphohydrolases that act upon inositol pyrophosphates.FEBS letters · 2026Review
- Laser microdissection-based multi-omics integration unveils the pathological atlas and tumor differentiation network of adamantinomatous craniopharyngioma.Acta neuropathologica communications · 2026Article
- Experimental Primary Brain Calcification Model and Its Application to Pathogenesis Mechanism Analysis and Therapeutic Research.Neurology international · 2025Review
- Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease.Clinical science (London, England : 1979) · 2025Review
- KIDINS220 and InsP8 safeguard the stepwise regulation of phosphate exporter XPR1.Molecular cell · 2025Article
- Expression of miRNA in the Semitendinosus Muscle of Cattle Breeds with Varying Intramuscular Fat Deposition.Genes · 2025Article
- RBM15-mediated m6A modification of XPR1 promotes the malignant progression of lung adenocarcinoma.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- The identification of XPR1 as a voltage- and phosphate-activated phosphate-permeable ion channel.Nature communications · 2025Article
- Structure and function of human XPR1 in phosphate export.Nature communications · 2025Article
- Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate.Nature communications · 2025Article
- Transport and InsPNature communications · 2025Article
- Structural basis of phosphate export by human XPR1.Nature communications · 2025Article
- Structural insights into the mechanism of phosphate recognition and transport by XPR1.Nature communications · 2025Article
- Enabling Technologies for the Dissection of Inositol Pyrophosphate Physiology.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Review
- Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8.Cell reports · 2024Article
- Is XPR1 mediating phosphate efflux?Pflugers Archiv : European journal of physiology · 2024Article
- Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.Nature communications · 2024Article
- Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis.Brain pathology (Zurich, Switzerland) · 2023Article
- Expanding the phenotype associated with biallelic SLC20A2 variants.European journal of human genetics : EJHG · 2023Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters with the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis, and we identified XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of WT SLC20A2 increased phosphate uptake, as expected, but also unexpectedly increased phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1 KO cells. Elevated ATP levels are a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with WT XPR1 but not with XPR1 harboring a mutated PP-IP-binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (
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