Affinage

P2RX1

P2X purinoceptor 1 · UniProt P51575

Length
399 aa
Mass
45.0 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RX1 (P2X1) is an ATP-gated, non-selective cation channel that couples extracellular nucleotide signals to calcium influx in smooth muscle, platelets, and immune cells (PMID:10638758, PMID:14500714, PMID:20660288). The functional channel assembles as a homotrimer in the endoplasmic reticulum, an architecture shared across the P2X family and confirmed by cross-linking and blue native PAGE (PMID:9606184, PMID:15313628, PMID:12488557); P2X1 subunits also co-assemble into heterotrimers with P2X5 or P2X4 to generate channels with distinct kinetics and pharmacology (PMID:9855626, PMID:10336430, PMID:18495881, PMID:15686495). Assembly and surface delivery depend on N-glycosylation and on five extracellular disulfide bonds, one of which (C261-C270) is required for cell-surface trafficking (PMID:11809854, PMID:10942758). The extracellular loop forms the ATP binding site, with discrete basic and aromatic residues coordinating the nucleotide and adenine ring and a cysteine-rich head domain that physically moves during gating and desensitization (PMID:14699168, PMID:22745172, PMID:21690089, PMID:19519776); the ectodomain confers intrinsically nanomolar ATP sensitivity that is masked in the intact receptor by rapid desensitization following a closed-open-desensitized pathway (PMID:14625300, PMID:12719485). Channel gating and responsiveness are tuned by membrane and cytoplasmic determinants: cholesterol-rich lipid rafts sensed through the intracellular N-terminus, direct PI(4,5)P2 binding to the C-terminus, the actin cytoskeleton, HSP90-dependent trafficking, GPCR-driven phosphorylation of an accessory protein, and agonist-induced dynamin-dependent recycling (PMID:16006561, PMID:18523136, PMID:20699225, PMID:22851178, PMID:15144237, PMID:20374431). Physiologically, P2X1 mediates sympathetic neurogenic contraction of vas deferens, bladder, and resistance arteries, and underlies renal afferent arteriolar autoregulation, with its loss causing male infertility from impaired vas deferens contraction (PMID:10638758, PMID:11090125, PMID:12435812, PMID:16920810, PMID:14679185, PMID:24297884). In blood and immune cells, P2X1 amplifies platelet activation by generating Ca2+ influx that potentiates Gq-coupled receptor signaling and ERK2/MLC-dependent secretion (PMID:14500714, PMID:24923466), drives neutrophil chemotaxis and extravasation via RhoA/Rho-kinase-dependent myosin light chain phosphorylation (PMID:19635923, PMID:25480563), contributes to thrombosis through cooperation between platelet and neutrophil P2X1 (PMID:25150292), sustains T-cell Ca2+ entry and NFAT/IL-2 signaling at the immune synapse (PMID:20660288), and regulates innate lymphoid cell IL-22 secretion supporting liver regeneration (PMID:26853442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Established the fundamental quaternary structure of P2X1, answering how subunits assemble into a functional receptor.

    Evidence Chemical cross-linking, blue native PAGE, and His-tag purification of P2X1 expressed in Xenopus oocytes

    PMID:9606184

    Open questions at the time
    • Did not resolve atomic-level subunit contacts
    • Hexamers seen in detergent left open whether trimer aggregation is physiological
  2. 1999 High

    Showed P2X1 is not obligately homomeric, defining heteromeric assembly partners that diversify channel properties.

    Evidence Reciprocal co-immunoprecipitation/co-purification of epitope-tagged P2X1 and P2X5 plus electrophysiology in HEK293 cells and oocytes

    PMID:10336430 PMID:9855626

    Open questions at the time
    • Stoichiometry of P2X1 within the heteromer not defined
    • Native tissue evidence for the heteromer not established here
  3. 2000 High

    Defined the in vivo physiological role of P2X1, answering whether the channel is required for smooth muscle function and fertility.

    Evidence Targeted P2X1 knockout mice with fertility testing and vas deferens/bladder smooth muscle contraction and current assays

    PMID:10638758 PMID:11090125

    Open questions at the time
    • Did not establish the downstream contractile signaling pathway
    • Infertility traced to reduced ejaculate sperm, not channel function in sperm
  4. 2003 High

    Resolved the apparent paradox of P2X1 potency, showing the ectodomain confers nanomolar ATP sensitivity masked by rapid desensitization.

    Evidence Non-desensitizing P2X2/P2X1 chimera electrophysiology and kinetic modeling of a closed-open-desensitized scheme in oocytes

    PMID:12719485 PMID:14625300

    Open questions at the time
    • Structural basis of the desensitized state not resolved
    • Whether nanomolar sensitivity operates in native cells under physiological ATP exposure not established
  5. 2003 High

    Located physiological autoregulation to P2X1, connecting tubuloglomerular feedback to ATP-gated vasoconstriction in the kidney.

    Evidence P2X1 KO mice and NF279 blockade in the juxtamedullary nephron preparation

    PMID:14679185

    Open questions at the time
    • Source and kinetics of ATP delivery to P2X1 in the nephron not fully defined
  6. 2004 High

    Identified membrane and cytoplasmic determinants that tune P2X1 responsiveness beyond agonist binding.

    Evidence Lipid raft fractionation with cholesterol depletion and GPCR co-expression with phosphorylation labeling in oocytes/HEK293 cells

    PMID:15144237 PMID:16006561

    Open questions at the time
    • Identity of the phosphorylated accessory protein not determined
    • Molecular link between raft localization and gating not mapped in these studies
  7. 2008 High

    Mapped the ATP and antagonist binding architecture and PI(4,5)P2 regulation, distinguishing residues governing binding, gating, and lipid modulation.

    Evidence Cysteine scanning, radiolabeled azido-ATP binding, MTS accessibility, species-swap mutagenesis, and inside-out macropatch PI(4,5)P2 application

    PMID:14699168 PMID:18523136 PMID:18765669 PMID:19519776

    Open questions at the time
    • No high-resolution P2X1 structure to anchor the binding model
    • Endogenous regulator of PI(4,5)P2 levels at the channel not identified
  8. 2009 High

    Defined P2X1 signaling in neutrophil migration, linking the channel to RhoA/Rho-kinase-driven rear retraction.

    Evidence P2X1 KO neutrophils, Rho kinase inhibitors, RhoA and MLC phosphorylation assays, and in vivo peritoneal recruitment

    PMID:19635923

    Open questions at the time
    • Mechanism coupling Ca2+ influx to spatially restricted RhoA activation at the rear not resolved
  9. 2012 High

    Demonstrated conformational dynamics of the cysteine-rich head domain and HSP90-dependent trafficking, linking structure motion and chaperone control to function.

    Evidence Voltage clamp fluorometry of head-domain residues and HSP90 inhibition with imaging, electrophysiology, and platelet Ca2+ assays

    PMID:20374431 PMID:22745172 PMID:22851178

    Open questions at the time
    • How HSP90 engages the intracellular termini mechanistically not defined
    • Coupling of head-domain motion to the transmembrane gate not fully resolved
  10. 2014 High

    Established P2X1 as an amplifier of platelet and thrombotic signaling and a cell-autonomous driver of neutrophil extravasation.

    Evidence P2X1 KO platelets and neutrophils, adoptive transfer, laser-injury thrombosis and endotoxemia intravital models, and Ca2+ superadditivity assays

    PMID:14500714 PMID:24923466 PMID:25150292 PMID:25480563

    Open questions at the time
    • Molecular mechanism of P2X1-IP3R/PLC potentiation not precisely defined
    • Relative contribution of platelet versus neutrophil P2X1 across thrombotic contexts not fully partitioned
  11. 2016 Medium

    Extended P2X1 function to innate lymphoid cells, linking ATP sensing to IL-22-dependent liver regeneration.

    Evidence In vivo P2X1 antagonism in Rag-deficient mice with partial hepatectomy and ex vivo IL-22 secretion assays

    PMID:26853442

    Open questions at the time
    • Pharmacological inhibition rather than ILC-specific genetic deletion
    • Signaling pathway from P2X1 Ca2+ entry to IL-22 transcription not defined
  12. 2021 Medium

    Revealed that P2X1 loss reprograms neutrophils toward immunosuppressive and pro-injury phenotypes through metabolic and Nrf2/PD-L1 changes.

    Evidence RNA-seq, P2RX1 KO mice, T-cell suppression assays, and renal ischemia-reperfusion and PDAC metastasis models

    PMID:33420030 PMID:34091010

    Open questions at the time
    • Mechanism remains partly correlative from KO and transcriptomics
    • Direct channel-activity link to Nrf2 induction and mitochondrial metabolism not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse cytoplasmic and membrane regulators (lipid rafts, PI(4,5)P2, HSP90, the actin cytoskeleton, accessory-protein phosphorylation) are integrated to set P2X1 gating and desensitization in native cells remains unresolved.
  • No high-resolution structure of human P2X1 in the timeline
  • Accessory phosphoprotein unidentified
  • Integration of regulatory inputs into a unified gating model not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-397014 Muscle contraction 3
Partners
HSP90P2RX4P2RX5P2RY1
Complex memberships
P2X1 homotrimerP2X1/P2X4 heterotrimerP2X1/P2X5 heterotrimer

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 P2X1 receptors form stable homotrimers as their fundamental quaternary structure. Chemical cross-linking with DTSSP and blue native PAGE of His-tagged P2X1 from Xenopus oocytes demonstrated quantitative homotrimeric assembly. Trimerization occurs in the endoplasmic reticulum, and the plasma membrane form is also a homotrimer. n-Octylglucoside solubilization revealed hexamers, suggesting trimers can aggregate. Chemical cross-linking, blue native PAGE, His-tag purification, [35S]-methionine labeling, Xenopus oocyte expression The EMBO journal High 9606184
1998 P2X1 and P2X5 subunits co-assemble to form a novel heteromeric ATP-gated ion channel with distinct functional properties: biphasic currents with a pronounced non-desensitizing plateau phase, shifted EC50 for alpha,beta-me-ATP, distinct from either homomeric channel. Co-immunoprecipitation confirmed physical association of epitope-tagged P2X1 and P2X5. Co-immunoprecipitation of epitope-tagged subunits, whole-cell patch clamp in HEK293 cells Molecular pharmacology High 10336430 18495881 9855626
1999 Rat P2X1 and P2X5 subunits physically co-assemble to form heteromeric P2X1+5 ATP-gated channels, demonstrated by reciprocal subunit-specific co-purification of epitope-tagged subunits from HEK293 cells. The heteromeric channel has slowly desensitizing currents sensitive to alpha,beta-methylene ATP (EC50=1.1 µM) and TNP-ATP (IC50=64 nM), properties distinct from either homomeric channel. Reciprocal co-purification of epitope-tagged subunits, two-electrode voltage clamp in Xenopus oocytes The Journal of biological chemistry High 10336430
2000 P2X1 receptors are essential for normal male reproductive function. Male P2X1 knockout mice show ~90% reduction in fertility due to reduced sperm in ejaculate (not sperm dysfunction). Contraction of vas deferens to sympathetic nerve stimulation is reduced up to 60% and responses to P2X receptor agonists are abolished in P2X1-deficient mice. Targeted gene deletion (P2X1 KO mice), fertility testing, smooth muscle contraction assays Nature High 10638758
2000 Homomeric P2X1 receptors underlie the P2X receptor phenotype in mouse urinary bladder smooth muscle. P2X receptor-mediated inward currents and contractions were abolished in bladder smooth muscle from P2X1-deficient mice, while muscarinic contractions were unaffected. P2X1 KO mice, whole-cell patch clamp, smooth muscle contraction assays, immunohistochemistry British journal of pharmacology High 11090125
2002 Ten conserved cysteine residues in the extracellular loop of the human P2X1 receptor form five disulfide bonds (proposed pairs: C117-C165, C126-C149, C132-C159, C217-C227, C261-C270). Disruption of the C261-C270 bond severely reduces cell-surface trafficking. Wild-type receptors showed no free cysteines by MTSEA-biotin labeling, indicating all are disulfide-bonded. Cysteine-to-alanine mutagenesis, MTSEA-biotin labeling of free cysteines, cell-surface expression assays in Xenopus oocytes Molecular pharmacology High 11809854
2003 The P2X1 ectodomain confers nanomolar ATP sensitivity (EC50 ~3.3 nM for steady-state activation), which is masked by rapid desensitization in the intact receptor. Using a non-desensitizing P2X2/P2X1 chimera incorporating the entire P2X1 ectodomain, stationary currents revealed >200-fold higher ATP potency than observed from peak currents of native P2X1. Agonist deactivation rates reflect unbinding rates and define true agonist potency. Chimeric receptor electrophysiology (P2X2/P2X1 chimera), two-electrode voltage clamp in Xenopus oocytes The Journal of biological chemistry High 14625300
2003 Activation and desensitization of P2X1 follow the same reaction pathway (C-O-D model: closed-open-desensitized) without significant direct C-to-D transition. Desensitization at steady-state has K1/2 of 3.2 nM, while peak current EC50 is 0.7 µM, demonstrating that apparent micromolar potency is an artifact of fast desensitization under non-steady-state conditions. Two-electrode voltage clamp with rapid solution exchange in Xenopus oocytes, kinetic modeling The Journal of general physiology High 12719485
2003 Basic residues Lys-68, Phe-185, Phe-291, Arg-292, and Lys-309 contribute to ATP ligand binding at P2X1 receptors. Phe-185 and Phe-291 coordinate binding of the adenine ring. Mutants F195A and W259A failed to form detectable channels at the cell surface. These findings were established using alanine substitution mutagenesis combined with partial agonist analysis (BzATP, Ap5A) to distinguish binding from gating. Alanine replacement mutagenesis, two-electrode voltage clamp in Xenopus oocytes, partial agonist pharmacology The Journal of biological chemistry High 14699168
2004 P2X1 receptors are present in cholesterol-rich lipid rafts in smooth muscle (rat tail artery, vas deferens, bladder) and HEK293 cells. Cholesterol depletion with methyl-beta-cyclodextrin redistributed P2X1 from lipid rafts and reduced P2X1-mediated currents by >90% in HEK293 cells and contractions by ~50% in rat tail artery, while KCl-evoked contractions were unaffected. Sucrose density gradient fractionation, Western blot, cholesterol depletion with methyl-beta-cyclodextrin, patch clamp The Journal of biological chemistry High 16006561
2004 G-protein-coupled receptor (Gαq-coupled mGluR1α, P2Y1, P2Y2) stimulation potentiates P2X1 receptor currents by up to 250% via a PKC-independent, staurosporine-sensitive mechanism. P2X1 receptors are basally phosphorylated but this phosphorylation level is unaffected by phorbol ester treatment, indicating that regulation occurs via phosphorylation of an accessory protein rather than direct channel phosphorylation. Co-expression in Xenopus oocytes, two-electrode voltage clamp, PLC inhibitor (U-73122), PKC inhibitors, radiolabeling of phosphorylated proteins in HEK293 cells The Biochemical journal High 15144237
2004 P2X1 and P2X4 subunits form heteromeric trimeric complexes. Co-purification of hexahistidyl-tagged P2X1 with P2X4 was demonstrated, and BN-PAGE confirmed both subunits reside in trimers of the same size. The heteromeric P2X1+4 receptor has kinetics resembling homomeric P2X4 but pharmacology similar to P2X1 (sensitive to suramin and TNP-ATP, activated by alpha,beta-methylene ATP with slow desensitization). His-tag co-purification, blue native PAGE, two-electrode voltage clamp in Xenopus oocytes Journal of neurochemistry High 15686495
2004 Trimeric architecture is the structural hallmark of functional homomeric and heteromeric P2X receptors. P2X1, P2X2, P2X3, P2X4, and P2X5 all assemble as homotrimers; co-expressed P2X1 and P2X2 form heterotrimers that are exported to the plasma membrane. P2X6 subunits that cannot form functional homomeric channels are retained in the ER as apparent tetramers/aggregates. BN-PAGE, biochemical analysis of co-expressed subunits Journal of molecular biology High 15313628
2003 P2X1 receptor mediates afferent arteriolar autoregulatory vasoconstriction in kidney. Blockade of P2X1 receptors with NF279 abolished pressure-mediated vasoconstriction, and P2X1 KO mice showed significantly blunted autoregulatory responses to increased renal perfusion pressure. Tubuloglomerular feedback signals are coupled to autoregulatory preglomerular vasoconstriction through ATP-mediated P2X1 activation. P2X1 KO mice, juxtamedullary nephron technique, NF279 pharmacological blockade, papillectomy/furosemide The Journal of clinical investigation High 14679185
2009 P2X1 ion channels promote neutrophil chemotaxis through RhoA GTPase activation and Rho kinase-dependent myosin light chain phosphorylation at the cell rear. P2X1 agonists activated RhoA and caused reversible MLC phosphorylation in human and mouse neutrophils. P2X1-/- neutrophils showed impaired trailing edge retraction and reduced migration speed. In vivo, neutrophil recruitment was impaired in P2X1 KO mice following E. coli injection. P2X1 KO mice, Boyden chamber chemotaxis assays, RhoA activation assay, MLC phosphorylation, Rho kinase inhibitors (Y27632, H1152), whole-cell patch clamp, in vivo peritoneal recruitment Journal of immunology High 19635923
2000 P2X1 receptor undergoes agonist-induced internalization. P2X1-GFP chimera showed spontaneous formation of synaptic-size clusters (4-6 µm) in plasma membranes of oocytes and HEK293 cells. Exposure to alpha,beta-meATP (10-20 min) with monensin led to disappearance of P2X1-GFP fluorescence from the cell surface, indicating receptor internalization. GFP chimera live cell imaging, confocal microscopy, agonist-stimulated internalization, adenoviral transduction Neuropharmacology Medium 10963749
2000 P2X1 receptors require N-glycosylation for assembly and function. Four N-glycosylation sites exist (Asn153, Asn184, Asn210, Asn300); only Asn300 acquires complex-type carbohydrates. Elimination of Asn153 diminishes and Asn210 increases functional expression; elimination of Asn210 causes 3-fold reduction in ATP potency. Simultaneous elimination of three or four sites severely impairs receptor formation. Glycan minus mutants still migrate as homotrimers on BN-PAGE. Site-directed mutagenesis of N-glycosylation sites, SDS-PAGE, BN-PAGE, two-electrode voltage clamp in Xenopus oocytes The Journal of biological chemistry High 10942758
2000 Deletion of a single leucine from a stretch of four leucines in the second transmembrane domain (TM2, residues 351-354) of the P2X1 receptor generates a naturally occurring dominant negative mutant. The mutant localizes correctly to the plasma membrane but fails to conduct current. When co-expressed with wild-type P2X1 in Xenopus oocytes, it exerts a dose-dependent dominant negative effect on ATP-evoked channel activity. Site-directed mutagenesis, confocal microscopy (plasma membrane localization), voltage clamp in HEK293 cells and Xenopus oocytes The Journal of biological chemistry High 10816552
2003 P2X1-mediated ERK2 activation amplifies collagen-induced platelet secretion by enhancing myosin light chain kinase activation. P2X1 agonist alpha,beta-meATP caused rapid Ca2+-dependent MLC phosphorylation requiring Ca2+/CaM-dependent MLC kinase (inhibited by W-7 but not Rho kinase inhibitor HA-1077). P2X1-dependent ERK2 activation contributes to MLC kinase activation; desensitization of P2X1 or blockade of ERK2 phosphorylation attenuated MLC phosphorylation, degranulation, and aggregation. Washed human platelet assays, kinase inhibitors (W-7, ML-7, U0126, PP1, GF109203-X), transmission electron microscopy, MLC phosphorylation assay The Journal of biological chemistry High 14500714
2002 P2X1 homomeric receptors underlie the P2X receptor phenotype in mouse mesenteric artery smooth muscle. ATP and alpha,beta-meATP evoked transient inward currents and constrictions in wild-type but not P2X1 KO mesenteric arteries. P2X1 receptors contribute approximately 50% to sympathetic neurogenic vasoconstriction. P2X1 KO mice, smooth muscle patch clamp, tension recordings, nerve stimulation Molecular pharmacology High 12435812
2005 P2X1 receptors mediate junctional Ca2+ transients (jCaTs) in smooth muscle cells adjacent to perivascular sympathetic nerves in mesenteric small arteries. In P2X1 KO arteries, neither electrical field stimulation nor alpha-latrotoxin elicited jCaTs. The initial rapid, transient component of biphasic sympathetic neurogenic vasoconstriction was absent in P2X1 KO arteries. P2X1 KO mice, confocal microscopy of fluo-4 fluorescence, electrical field stimulation, alpha-latrotoxin stimulation American journal of physiology. Heart and circulatory physiology High 16920810
2008 Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] directly modulates P2X1 receptor function through binding to the proximal intracellular C-terminus, with Lys364 as a critical determinant. Depletion of PI(4,5)P2 with wortmannin significantly decreased P2X1 current amplitude and recovery; direct application of PI(4,5)P2 to inside-out macropatches rescued currents from rundown. PI(4,5)P2 (but not PI(3,4,5)P3) reversed the functional impact. Wortmannin treatment in isolated mesenteric artery and Xenopus oocytes, inside-out macropatch recording with direct PI(4,5)P2 application, point mutagenesis of Lys364 Molecular pharmacology High 18523136
2010 Cholesterol sensitivity of P2X1 receptors (but not P2X2, P2X3, P2X4) is mediated by the intracellular N-terminal region between the conserved PKC site and the first transmembrane segment (residues 20-23 and 27-29). Chimeric P2X1/P2X2 receptors and point mutations in this region removed cholesterol sensitivity. Cholesterol depletion does not alter ATP sensitivity or cell surface expression, but impairs channel opening/gating. Chimeric receptor construction, point mutagenesis, methyl-beta-cyclodextrin treatment, patch clamp in HEK293 cells The Journal of biological chemistry High 20699225
2012 The cysteine-rich head domain of P2X1 moves during receptor activation and desensitization. Voltage clamp fluorometry of residues N120-I125 labeled with tetramethyl-rhodamine-maleimide showed fluorescence changes upon agonist application: N120C and G123C showed fast decreases correlating with channel activation; P121C and I125C showed slow increases correlating with desensitization. TNP-ATP caused large fluorescence changes at N120C, E122C, G123C, confirming proximity to the ATP binding site. Voltage clamp fluorometry, cysteine substitution mutagenesis, fluorophore labeling (TMRM), Xenopus oocyte expression, molecular modeling Proceedings of the National Academy of Sciences of the United States of America High 22745172
2011 Cysteine scanning of residues Glu52-Gly96 mapped the ATP binding site of P2X1: K68C, K70C, and F92C reduced ATP potency; several mutants at the back of the proposed binding site reduced partial agonist efficacy. MTS-reactive mutants were concentrated around the ATP binding pocket and on strands connecting to transmembrane regions lining the central vestibule, suggesting the central vestibule base contributes to gating. G60C with positively charged MTS reagent increased ATP sensitivity, supporting a role for the central vestibule in gating. Cysteine scanning mutagenesis, MTS reagent accessibility, molecular docking in silico, two-electrode voltage clamp in Xenopus oocytes The Journal of biological chemistry High 21690089
2012 Selective antagonism of P2X1 by NF449 and suramin requires a cluster of positively charged residues (Lys111, Lys127, Lys138, Lys148) at the base of the cysteine-rich head region. Chimeras replacing this region reduced NF449 sensitivity 1000-fold. The single substitution K138E (either alone or in combination) largely accounted for the difference in suramin sensitivity between human and mouse P2X1 receptors. Chimeric receptor construction, point mutagenesis, two-electrode voltage clamp in Xenopus oocytes British journal of pharmacology High 21671897
2010 P2X1 receptor trafficking and recycling regulate receptor responsiveness. FRAP studies showed P2X1-eGFP is highly mobile at the cell surface (tau ~60 s, ~75% recovery). Agonist-induced Ca2+ influx doubled FRAP recovery rate. Brefeldin A (trafficking inhibitor) reduced recovery and prolonged desensitization recovery, while dynasore (dynamin inhibitor) reduced recovery only after agonist stimulation, indicating a role for receptor recycling in resensitization. FRAP of P2X1-eGFP in HEK293 cells, pharmacological inhibition of trafficking (brefeldin A, dynasore, cycloheximide) Journal of neurochemistry High 20374431
2012 HSP90 inhibition (geldanamycin, radicicol) reduces P2X1 receptor trafficking and currents. Geldanamycin reduced P2X1 currents by ~70-85% in HEK293 cells, reduced cell surface expression, and almost abolished P2X1-eGFP movement. P2X1/P2X2 chimeras identified the intracellular N and C termini as determinants of HSP90 sensitivity. In platelets, HSP90 inhibition reduced P2X1-mediated Ca2+ increases by 40-45% and attenuated collagen-induced Ca2+ responses. Photoactivatable GFP imaging, patch clamp, cell surface expression assay, chimeric receptor analysis, human platelet Ca2+ measurements The Journal of biological chemistry High 22851178
2010 TCR stimulation causes translocation of P2X1 and P2X4 receptors to the immune synapse, while P2X7 remains uniformly distributed. Inhibition, mutation, or silencing of P2X1 and P2X4 receptors inhibits Ca2+ entry, NFAT activation, and IL-2 synthesis. Pannexin-1 hemichannel inhibition suppresses TCR-induced ATP release and T-cell activation, placing P2X1 in an autocrine ATP feedback loop at the immune synapse. Confocal microscopy (receptor translocation), siRNA silencing, Ca2+ imaging, NFAT reporter assay, IL-2 ELISA Blood High 20660288
2013 Simultaneous genetic deletion of P2X1-purinoceptors and alpha1A-adrenoceptors produces 100% male infertility without effects on sexual behavior or sperm quality. This confirms that P2X1 and alpha1A-adrenergic signaling are both required for sympathetically mediated sperm transport through the vas deferens during ejaculation. Neither single KO was sufficient for complete contraception. Double KO mice, fertility testing, ICSI of double KO sperm into WT ova Proceedings of the National Academy of Sciences of the United States of America High 24297884
2014 P2X1 receptors on neutrophils are required for neutrophil extravasation during LPS-induced endotoxemia. Intravital microscopy showed a defect in LPS-induced neutrophil emigration from cremaster venules in P2X1-/- mice. Adoptive transfer experiments demonstrated that the absence of P2X1 specifically on neutrophils was responsible for the emigration defect. P2X1 KO mice, intravital microscopy, adoptive transfer of fluorescently labeled neutrophils, cytokine measurement Journal of immunology High 25480563
2014 P2X1 receptors on both PMNs and platelets are required for thrombosis. In P2X1-deficient mice, neutrophil recruitment and fibrin generation at laser-induced endothelial injury sites were impaired. Infusion of WT PMNs into P2X1-deficient mice increased fibrin generation but not full thrombus formation; restoration required both WT platelets and WT PMNs, establishing that P2X1 on both cell types contributes to thrombosis. P2X1 KO mice, adoptive transfer of WT/KO platelets and PMNs, laser-induced injury thrombosis model, in vivo imaging Blood High 25150292
2014 Ca2+ influx through P2X1 receptors amplifies P2Y1-evoked Ca2+ signaling via potentiation of IP3 receptors and/or PLC, not via Na+ influx or membrane depolarization. This superadditive Ca2+ response was observed in both platelets and HEK293 cells; P2X1 also enhanced Ca2+ responses when co-stimulated with PAR1 and M1 muscarinic receptors. The amplification persisted for up to 60 seconds after P2X1 activation. Human platelet and HEK293 cell Ca2+ measurements, pharmacological inhibitors (PKC, Rho-kinase, ERK1/2), P2X1 KO mouse platelets, ionomycin mimicry Molecular pharmacology High 24923466
1998 The actin cytoskeleton modulates P2X1 receptor gating kinetics. P2X1 receptors expressed in HEK293 cells showed faster activation and desensitization kinetics on day 1 post-passage (round cells) but slower, more native-like kinetics on day 2 (flat cells). Treatment with cytochalasins B or D reverted kinetics to the rapid phenotype. Two TM2 pore-domain point mutants were unable to effect this kinetic shift. Whole-cell patch clamp in HEK293 cells, cytochalasin treatment, point mutagenesis of pore domain residues The Journal of physiology Medium 9625863
2001 ATP is the principal physiological agonist at platelet P2X1 receptors. The splice variant P2X1del fails to form functional ion channels. ADP does not contribute to the rapid ionotropic P2X receptor-mediated response in platelets, contrary to a previous report. These findings were established by functional Ca2+ measurements and detection limits for P2X1del in human platelets. Intracellular Ca2+ measurements in human platelets, RT-PCR, electrophysiology in Xenopus oocytes Blood Medium 12907444
2005 P2X1 receptors are localized to lipid rafts in smooth muscle preparations and HEK293 cells, co-localizing with flotillin-1 and -2. This localization creates a signaling microdomain near sympathetic nerve varicosities essential for maintaining P2X1 receptor function and mediating neurogenic vasoconstriction. Discontinuous sucrose density gradient fractionation, Western blot, cholesterol measurements The Journal of biological chemistry High 16006561
2009 T186, F188, and K190 in the conserved AsnPheThrPhiPhixLys motif of the P2X1 extracellular loop contribute to ATP binding (their mutation reduced ATP potency and MTS reagent effects were consistent with altered binding). F185 and F195 contribute to agonist-evoked conformational changes (gating). The region Thr186-Ser192 likely forms a beta sheet and ATP blocks accessibility of these residues. Cysteine scanning mutagenesis (residues 181-200), MTS reagent accessibility, [32P]-2-azido ATP binding assay, MTSEA-biotin accessibility probing in Xenopus oocytes Journal of neurochemistry High 19519776
2016 P2X1-regulated IL-22 secretion by innate lymphoid cells (conventional NK cells and ILC type 1) is required for efficient liver regeneration after partial hepatectomy. In vivo specific inhibition of P2X1 was associated with decreased IL-22 secretion, elevated liver injury, and impaired regeneration. Extracellular ATP released after resection signals through P2X1 on innate lymphoid cells to induce IL-22. P2X1 antagonist in vivo, Rag1-/- and Rag2-/-γc-/- mice, ex vivo IL-22 secretion assay, partial hepatectomy mouse model Hepatology Medium 26853442
1996 Functional P2X1 receptors are expressed in differentiated HL60 cells and are chronically desensitized by constitutive ATP release from these cells. ATP-evoked P2X1 currents (rapid desensitization, mimicked by alpha,beta-methylene-ATP) were only detected after pretreatment with apyrase (destroys extracellular ATP) or suramin (P2X antagonist). Direct luciferin-luciferase measurement confirmed ATP release. Whole-cell patch clamp, radioligand binding, immunohistochemistry, luciferin-luciferase ATP assay Blood Medium 8639881
2008 K138 in the ectodomain of human P2X1 is a key residue for suramin and NF449 binding. Substitution K138E in human P2X1 significantly reduced sensitivity to both antagonists, and introduction of K138 into the corresponding mouse residue greatly increased sensitivity, explaining species differences in antagonist pharmacology. Point mutagenesis, two-electrode voltage clamp in HEK293 cells The Journal of biological chemistry High 18765669
2003 P2X1 concatamers of 2-6 subunits are retained as aggregates in the ER. Only byproducts (monomers and dimers) from concatamer cleavage combine to form trimeric complexes equal in mass to homotrimeric P2X1, and these byproduct trimers account for all ATP-gated currents from concatamer-expressing oocytes. This strongly corroborates trimeric architecture and reveals a pitfall of the concatamer approach. BN-PAGE, biochemical analysis of Xenopus oocyte-expressed concatamers, electrophysiology Molecular pharmacology High 12488557
2021 P2RX1-deficient neutrophils in PDAC liver metastases upregulate immunosuppressive molecules including PD-L1 and show enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and is associated with PD-L1 expression and metabolic reprogramming, defining a mechanism by which loss of P2RX1 shifts neutrophils to an immunosuppressive phenotype. RNA sequencing of murine and human PDAC liver metastasis neutrophils, P2RX1 KO mice, in vitro OT1 CD8+ T-cell suppression assay, anti-PD-1 neutralization Nature communications Medium 33420030
2021 P2RX1 activation promotes platelet ATP release, which supports neutrophil glycolytic metabolism and NETs generation, creating a metabolic interaction between platelets and neutrophils that contributes to renal ischemia-reperfusion injury. P2RX1 KO mice show preserved mitochondrial dynamics and reduced NETs formation after renal IRI. P2RX1 KO mice, RNA sequencing, mitochondrial morphology assessment, NETs quantification Pharmacological research Medium 34091010

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. The EMBO journal 468 9606184
2000 Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature 311 10638758
2010 Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 271 20660288
1998 Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors. Molecular pharmacology 226 9614197
2005 Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 187 16000618
1996 Activation of receptor-operated cation channels via P2X1 not P2T purinoceptors in human platelets. The Journal of biological chemistry 168 8621673
2008 P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 142 18495881
2003 Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior. The Journal of clinical investigation 141 14679185
2000 P2X receptor expression in mouse urinary bladder and the requirement of P2X(1) receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. British journal of pharmacology 137 11090125
2002 Conserved cysteine residues in the extracellular loop of the human P2X(1) receptor form disulfide bonds and are involved in receptor trafficking to the cell surface. Molecular pharmacology 120 11809854
1998 Co-expression of P2X1 and P2X5 receptor subunits reveals a novel ATP-gated ion channel. Molecular pharmacology 112 9855626
2021 Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis. Nature communications 100 33420030
2004 Trimeric architecture of homomeric P2X2 and heteromeric P2X1+2 receptor subtypes. Journal of molecular biology 99 15313628
2002 P2X(1) receptor-deficient mice establish the native P2X receptor and a P2Y6-like receptor in arteries. Molecular pharmacology 96 12435812
2004 Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist. European journal of medicinal chemistry 91 15072843
2000 Distribution of P2X1, P2X2, and P2X3 receptor subunits in rat primary afferents: relation to population markers and specific cell types. Journal of chemical neuroanatomy 89 11118807
2005 Disruption of lipid rafts inhibits P2X1 receptor-mediated currents and arterial vasoconstriction. The Journal of biological chemistry 87 16006561
2003 ATP binding at human P2X1 receptors. Contribution of aromatic and basic amino acids revealed using mutagenesis and partial agonists. The Journal of biological chemistry 86 14699168
1998 Coexpression of mRNAs for P2X1, P2X2 and P2X4 receptors in rat vascular smooth muscle: an in situ hybridization and RT-PCR study. Journal of vascular research 85 9647332
2009 Functional evidence for the expression of P2X1, P2X4 and P2X7 receptors in human lung mast cells. British journal of pharmacology 80 19552691
2005 Biochemical and functional evidence for heteromeric assembly of P2X1 and P2X4 subunits. Journal of neurochemistry 79 15686495
2009 P2X1 ion channels promote neutrophil chemotaxis through Rho kinase activation. Journal of immunology (Baltimore, Md. : 1950) 77 19635923
1997 Presence of P2X1 purinoceptors in human platelets and megakaryoblastic cell lines. Thrombosis and haemostasis 77 9423802
2001 The ATP-gated P2X1 ion channel acts as a positive regulator of platelet responses to collagen. Thrombosis and haemostasis 75 11816716
1999 Functional and biochemical evidence for heteromeric ATP-gated channels composed of P2X1 and P2X5 subunits. The Journal of biological chemistry 75 10336430
2000 The suramin analogue NF279 is a novel and potent antagonist selective for the P2X(1) receptor. Neuropharmacology 74 10963748
1998 P2X1 purinoceptor in human platelets. Molecular cloning and functional characterization after heterologous expression. The Journal of biological chemistry 73 9565569
2000 P2X(1) receptor membrane redistribution and down-regulation visualized by using receptor-coupled green fluorescent protein chimeras. Neuropharmacology 71 10963749
1996 P2X1 receptor activation in HL60 cells. Blood 70 8639881
2003 Desensitization masks nanomolar potency of ATP for the P2X1 receptor. The Journal of biological chemistry 68 14625300
2002 A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors. British journal of pharmacology 68 11815371
2014 P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice. Blood 64 25150292
2001 Structure-activity relationships of pyridoxal phosphate derivatives as potent and selective antagonists of P2X1 receptors. Journal of medicinal chemistry 64 11462975
2003 Activation and desensitization of the recombinant P2X1 receptor at nanomolar ATP concentrations. The Journal of general physiology 62 12719485
2005 Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X1 receptor antagonist. Neuropharmacology 61 15721178
2001 NF449: a subnanomolar potency antagonist at recombinant rat P2X1 receptors. Naunyn-Schmiedeberg's archives of pharmacology 61 11521173
1999 Properties of the novel ATP-gated ionotropic receptor composed of the P2X(1) and P2X(5) isoforms. Molecular pharmacology 60 10496954
1998 The P2X1 receptor, an adenosine triphosphate-gated cation channel, is expressed in human platelets but not in human blood leukocytes. Blood 60 9558372
2004 G-protein-coupled receptor regulation of P2X1 receptors does not involve direct channel phosphorylation. The Biochemical journal 59 15144237
2003 P2X1-mediated ERK2 activation amplifies the collagen-induced platelet secretion by enhancing myosin light chain kinase activation. The Journal of biological chemistry 59 14500714
2003 NF449, a novel picomolar potency antagonist at human P2X1 receptors. European journal of pharmacology 58 12787824
2000 Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochimica et biophysica acta 58 11004484
2004 Emerging roles for P2X1 receptors in platelet activation. Platelets 57 15203715
2012 Involvement of the cysteine-rich head domain in activation and desensitization of the P2X1 receptor. Proceedings of the National Academy of Sciences of the United States of America 56 22745172
2003 Monomeric and dimeric byproducts are the principal functional elements of higher order P2X1 concatamers. Molecular pharmacology 53 12488557
2009 Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation. Thrombosis and haemostasis 50 20024498
2004 Renal autoregulation in P2X1 knockout mice. Acta physiologica Scandinavica 50 15283757
2000 A natural dominant negative P2X1 receptor due to deletion of a single amino acid residue. The Journal of biological chemistry 50 10816552
1999 Increase in cardiac P2X1-and P2Y2-receptor mRNA levels in congestive heart failure. Life sciences 50 10503935
2000 Roles of individual N-glycans for ATP potency and expression of the rat P2X1 receptor. The Journal of biological chemistry 49 10942758
1996 The human P2x1 receptor: molecular cloning, tissue distribution, and localization to chromosome 17. Biochimica et biophysica acta 49 8809107
2011 The P2X1 receptor and platelet function. Purinergic signalling 48 21484087
2020 Oleic and Linoleic Acids Induce the Release of Neutrophil Extracellular Traps via Pannexin 1-Dependent ATP Release and P2X1 Receptor Activation. Frontiers in veterinary science 47 32582772
2010 Lipid raft association and cholesterol sensitivity of P2X1-4 receptors for ATP: chimeras and point mutants identify intracellular amino-terminal residues involved in lipid regulation of P2X1 receptors. The Journal of biological chemistry 47 20699225
1998 A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X1 receptors. Journal of medicinal chemistry 46 9632352
2007 P2X1 and P2X4 receptor currents in mouse macrophages. British journal of pharmacology 44 17934511
2002 Cerebellar lesion up-regulates P2X1 and P2X2 purinergic receptors in precerebellar nuclei. Neuroscience 44 12421608
2014 The P2X1 receptor is required for neutrophil extravasation during lipopolysaccharide-induced lethal endotoxemia in mice. Journal of immunology (Baltimore, Md. : 1950) 42 25480563
2008 Platelet antistaphylococcal responses occur through P2X1 and P2Y12 receptor-induced activation and kinocidin release. Infection and immunity 42 18824536
2007 Identification of atropine- and P2X1 receptor antagonist-resistant, neurogenic contractions of the urinary bladder. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 17251425
2005 Contribution of conserved polar glutamine, asparagine and threonine residues and glycosylation to agonist action at human P2X1 receptors for ATP. Journal of neurochemistry 41 16371009
2012 Molecular basis of selective antagonism of the P2X1 receptor for ATP by NF449 and suramin: contribution of basic amino acids in the cysteine-rich loop. British journal of pharmacology 40 21671897
2011 Cysteine scanning mutagenesis (residues Glu52-Gly96) of the human P2X1 receptor for ATP: mapping agonist binding and channel gating. The Journal of biological chemistry 40 21690089
2013 Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice. Proceedings of the National Academy of Sciences of the United States of America 39 24297884
1998 The distribution of single P2x1-receptor clusters on smooth muscle cells in relation to nerve varicosities in the rat urinary bladder. Journal of neurocytology 39 11246492
2021 Targeting P2RX1 alleviates renal ischemia/reperfusion injury by preserving mitochondrial dynamics. Pharmacological research 38 34091010
2006 P2X1 stimulation promotes thrombin receptor-mediated platelet aggregation. Journal of thrombosis and haemostasis : JTH 38 16634759
2006 P2X1 receptors mediate sympathetic postjunctional Ca2+ transients in mesenteric small arteries. American journal of physiology. Heart and circulatory physiology 38 16920810
2001 Transient expression of P2X(1) receptor subunits of ATP-gated ion channels in the developing rat cochlea. Brain research. Developmental brain research 38 11248351
2010 P2X(1) receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo. American journal of physiology. Renal physiology 37 20335318
2002 Effects of enhanced P2X1 receptor Ca2+ influx on functional responses in human platelets. Thrombosis and haemostasis 37 12353081
2016 P2X1-regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration. Hepatology (Baltimore, Md.) 36 26853442
2008 Direct modulation of P2X1 receptor-channels by the lipid phosphatidylinositol 4,5-bisphosphate. Molecular pharmacology 36 18523136
1998 Identification of a P2X1 purinoceptor expressed on human platelets. Biochemical and biophysical research communications 35 9464249
2006 Differential sensitivity of human platelet P2X1 and P2Y1 receptors to disruption of lipid rafts. Biochemical and biophysical research communications 32 16546137
1998 Modulation of ATP-gated non-selective cation channel (P2X1 receptor) activation and desensitization by the actin cytoskeleton. The Journal of physiology 32 9625863
2011 P2X1 receptor-mediated vasoconstriction of afferent arterioles in angiotensin II-infused hypertensive rats fed a high-salt diet. Hypertension (Dallas, Tex. : 1979) 31 21321307
2008 The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine. The Journal of biological chemistry 31 18480058
2004 Vanilloid receptor like 1 (VRL1) immunoreactivity in mammalian retina: colocalization with somatostatin and purinergic P2X1 receptors. The Journal of comparative neurology 31 15174083
2012 Platelet Ca(2+) responses coupled to glycoprotein VI and Toll-like receptors persist in the presence of endothelial-derived inhibitors: roles for secondary activation of P2X1 receptors and release from intracellular Ca(2+) stores. Blood 30 22228626
2003 Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis. Blood 30 12907444
2003 Potentiation of platelet activation through the stimulation of P2X1 receptors. Journal of thrombosis and haemostasis : JTH 30 14675100
2014 Extracellular ATP induces intracellular alpha-synuclein accumulation via P2X1 receptor-mediated lysosomal dysfunction. Neurobiology of aging 29 25480524
2012 Expression of P2X₁ and P2X₄ receptors in rat trigeminal ganglion neurons. Neuroreport 29 22785548
2008 Ectodomain lysines and suramin block of P2X1 receptors. The Journal of biological chemistry 29 18765669
2010 P2X1 receptor mobility and trafficking; regulation by receptor insertion and activation. Journal of neurochemistry 28 20374431
2009 Contribution of the region Glu181 to Val200 of the extracellular loop of the human P2X1 receptor to agonist binding and gating revealed using cysteine scanning mutagenesis. Journal of neurochemistry 28 19519776
2008 Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes. Osteoarthritis and cartilage 28 18448363
2003 Pharmacological identification of P2X1, P2X4 and P2X7 nucleotide receptors in the smooth muscles of human umbilical cord and chorionic blood vessels. Placenta 28 12495655
2001 Smooth muscle does not have a common P2x receptor phenotype: expression, ontogeny and function of P2x1 receptors in mouse ileum, bladder and reproductive systems. Autonomic neuroscience : basic & clinical 28 11570704
2019 Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors. Neuropharmacology 27 31461640
2012 Immunosuppression preserves renal autoregulatory function and microvascular P2X(1) receptor reactivity in ANG II-hypertensive rats. American journal of physiology. Renal physiology 27 23269644
1996 A comparison of the binding characteristics of recombinant P2X1 and P2X2 purinoceptors. British journal of pharmacology 26 8842447
2014 Comparative analysis of P2X1, P2X2, P2X3, and P2X4 receptor subunits in rat nodose ganglion neurons. PloS one 25 24798490
2012 Heat shock protein 90 inhibitors reduce trafficking of ATP-gated P2X1 receptors and human platelet responsiveness. The Journal of biological chemistry 25 22851178
2025 LIPUS activated piezoelectric pPLLA/SrSiO3 composite scaffold promotes osteochondral regeneration through P2RX1 mediated Ca2+ signaling pathway. Biomaterials 24 39754966
2009 ATP induces P2X7 receptor-independent cytokine and chemokine expression through P2X1 and P2X3 receptors in murine mast cells. Journal of leukocyte biology 23 19164130
2009 P2X(1) receptor inhibition and soluble CD39 administration as novel approaches to widen the cardiovascular therapeutic window. Trends in cardiovascular medicine 23 19467446
2005 P2X1 receptors are closely associated with connexin 43 in human ventricular myocardium. International journal of cardiology 23 15686781
2014 Ca2+ influx through P2X1 receptors amplifies P2Y1 receptor-evoked Ca2+ signaling and ADP-evoked platelet aggregation. Molecular pharmacology 22 24923466

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