Affinage

P2RX3

P2X purinoceptor 3 · UniProt P56373

Length
397 aa
Mass
44.3 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RX3 encodes P2X3, an ATP-gated non-selective cation channel that serves as a principal transducer of nociceptive and chemosensory signals in primary sensory neurons (PMID:27626375, PMID:9721930). X-ray crystallography of human P2X3 in multiple conformational states resolved its full gating cycle and an intracellular 'cytoplasmic cap' that stabilizes the open state and forms lateral phospholipid-lined fenestrations for ion egress, and defined the binding modes of competitive antagonists TNP-ATP and A-317491 (PMID:27626375); a distinct negative allosteric pocket formed by the left flipper, lower body, and dorsal fin domains is exploited by the inhibitors AF-353 and AF-219 (and by aurintricarboxylic acid), while gefapixant (MK-7264) acts as a reversible, state-dependent allosteric antagonist (PMID:29674445, PMID:31461640, PMID:30927255). Channel activity is tuned by an acidic chamber that engages divalent ions with the ATP γ-phosphate to enable activation by ATP-divalent complexes and to prolong desensitization recovery (PMID:31232692). P2X3 assembles as homomers and as heteromeric P2X2/3 channels with distinct kinetics (PMID:9254665), localizes to cholesterol-dependent lipid raft microdomains that sustain its functional potentiation (PMID:15139024, PMID:21958474), and is targeted presynaptically in dorsal horn sensory terminals (PMID:9721930). Surface delivery is driven by an ATP→Ca2+→CaMKIIα cascade in which CaMKIIα binds the P2X3 N-terminus and phosphorylates Thr388 to promote caveolin-1 binding and membrane insertion (PMID:24755854), a trafficking step also engaged by Wnt5b/Ryk signaling (PMID:32979370). Receptor activity is further modulated by ecto-PKC phosphorylation of extracellular Thr134/Ser178 (potentiation) and Cdk5/p35-mediated serine phosphorylation (downregulation) (PMID:16120774, PMID:19960242), by G-protein-dependent cross-inhibition from metabotropic P2Y receptors (PMID:17351651), and by direct partners GPR151, ASIC3, TRPV1, and the inhibitory protein Pirt (PMID:34244727, PMID:29636447, PMID:23201260, PMID:26151598). Transcriptionally, CGRP upregulates P2X3 through a CaMKII-CREB-BDNF pathway (PMID:18460469), and the receptor functions in nociception, bladder activity, carotid body chemosensation, and cardiorespiratory regulation (PMID:26151598, PMID:36977675).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1997 High

    Established that P2X3 is not solely a homomeric channel but physically co-assembles with P2X2 into heteromers with distinct pharmacology, defining the receptor's subunit-composition repertoire.

    Evidence Baculovirus co-expression with epitope tags, cross-immunoprecipitation, and whole-cell electrophysiology

    PMID:9254665

    Open questions at the time
    • Stoichiometry of the heteromer not defined
    • In vivo prevalence of homomer vs heteromer in sensory neurons not resolved
  2. 1997 Medium

    Characterized the genomic architecture and chromosomal location of P2X3, providing the substrate for understanding its transcriptional regulation.

    Evidence Genomic library screening, RNase protection, primer extension, FISH (mouse)

    PMID:9300827

    Open questions at the time
    • Promoter elements driving cell-type-specific expression not functionally dissected
    • Mouse genomic structure may differ from human
  3. 1998 Medium

    Defined where P2X3 acts subcellularly — presynaptic sensory terminals in the dorsal horn — pinpointing it as a site of ATP-mediated sensory transmission.

    Evidence Electron microscopy immunocytochemistry of trigeminal ganglion and dorsal horn

    PMID:9721930

    Open questions at the time
    • Functional consequence of presynaptic localization not directly tested
    • Single-lab ultrastructural assignment
  4. 1998 Medium

    Identified GDNF as an extrinsic regulator that maintains P2X3 expression in sensory neurons, linking the receptor to neurotrophic control after injury.

    Evidence Immunohistochemistry with intrathecal GDNF infusion after sciatic axotomy

    PMID:9828090

    Open questions at the time
    • Transcriptional vs post-transcriptional mechanism of GDNF effect unresolved
    • GDNF receptor pathway to P2X3 not mapped
  5. 2001 Medium

    Extended P2X2/3 function beyond pain to peripheral chemosensation, showing ATP acts as a co-transmitter in carotid body hypoxic/hypercapnic signaling.

    Evidence RT-PCR, single-cell RT-PCR, co-culture electrophysiology, immunofluorescence, suramin blockade

    PMID:11744746

    Open questions at the time
    • Relative contribution of homomeric vs heteromeric channels to chemosensing not separated
    • Pharmacological blockade non-selective (suramin)
  6. 2005 Medium

    Demonstrated that extracellular kinase activity can directly potentiate P2X3 by phosphorylating ectodomain residues Thr134/Ser178, an unusual ecto-PKC mechanism upregulating channel current.

    Evidence Whole-cell patch-clamp, site-directed mutagenesis, molecular simulation

    PMID:16120774

    Open questions at the time
    • Identity and source of the ecto-kinase in vivo unclear
    • Physiological trigger for ectodomain phosphorylation not established
  7. 2006 Medium

    Clarified that PKC-mediated potentiation of P2X3 currents does not require direct phosphorylation of the receptor, implicating an indirect regulatory mechanism.

    Evidence Patch-clamp, calcium imaging, metabolic 32P labeling, in vitro kinase assay, immunoprecipitation

    PMID:17052768

    Open questions at the time
    • Intermediary substrate mediating indirect PKC effect not identified
    • Tension with ecto-PKC findings not reconciled
  8. 2007 Medium

    Revealed cross-talk between ionotropic and metabotropic purinergic signaling, with P2Y receptors inhibiting P2X3 via G-protein-facilitated desensitization.

    Evidence Whole-cell patch-clamp on HEK293-hP2X3 and rat DRG with intracellular GDP-β-S

    PMID:17351651

    Open questions at the time
    • Specific G-protein subunit and downstream effector not identified
    • Direct vs diffusible second-messenger coupling not distinguished
  9. 2004 Medium

    Showed P2X3 partitions into lipid raft microdomains, and that raft integrity sustains its current amplitude and desensitization kinetics, identifying membrane microenvironment as a determinant of channel function.

    Evidence Detergent-resistant membrane fractionation, sucrose gradients, cholesterol depletion; later patch-clamp/kinetic modeling in trigeminal neurons

    PMID:15139024 PMID:21958474

    Open questions at the time
    • Molecular tether anchoring P2X3 to rafts not identified
    • Effect of cholesterol depletion may be pleiotropic
  10. 2008 High

    Established a transcriptional axis whereby CGRP raises P2X3 levels via CaMKII-CREB signaling with BDNF as an intermediate, linking neuropeptide signaling to receptor abundance.

    Evidence Immunocytochemistry, dominant-negative CREB, anti-BDNF blockade, expression analysis in trigeminal cultures

    PMID:18460469

    Open questions at the time
    • Direct CREB occupancy on the P2X3 promoter not shown
    • Timescale linking transcription to functional current not defined
  11. 2009 Medium

    Identified Cdk5/p35 as a serine kinase that downregulates P2X3 current, adding negative phosphoregulation to the receptor's control logic.

    Evidence HEK co-transfection, whole-cell patch-clamp, phosphorylation assay

    PMID:19960242

    Open questions at the time
    • Phosphoacceptor serine residues not mapped
    • Endogenous neuronal relevance not tested in vivo
  12. 2009 Medium

    Showed phosphoinositides regulate P2X3 function indirectly, since unlike P2X2 the P2X3 C-terminus does not directly bind PIP2/PIP3.

    Evidence Patch-clamp across oocytes/HEK293/DRG, wortmannin inhibition, PIP2 application, lipid-binding assay

    PMID:19671169

    Open questions at the time
    • Intermediary linking phosphoinositides to P2X3 unidentified
    • Mechanism of wortmannin-induced current depression not fully resolved
  13. 2014 High

    Defined the activity-dependent trafficking pathway: P2X3-driven Ca2+ activates CaMKIIα, which binds the N-terminus and phosphorylates Thr388 to recruit caveolin-1 and drive membrane insertion, explaining use-dependent surface upregulation.

    Evidence Reciprocal co-IP, mutagenesis, caveolin-1 knockdown, confocal imaging, surface biotinylation in HEK293T and primary neurons

    PMID:24755854

    Open questions at the time
    • Vesicular route and SNARE machinery for insertion not defined
    • Reversal/internalization arm of the cycle not characterized
  14. 2016 High

    Resolved the complete P2X3 gating cycle at atomic resolution, defining resting/open/desensitized/antagonist-bound states, the cytoplasmic cap, ion-egress fenestrations, and competitive antagonist binding.

    Evidence X-ray crystallography of human P2X3 in multiple conformational states with functional validation

    PMID:27626375

    Open questions at the time
    • Structures of heteromeric P2X2/3 not solved
    • Dynamics of state transitions inferred rather than directly observed
  15. 2018 High

    Localized a druggable negative allosteric pocket (LF/LB/DF domains) that allosteric antagonists exploit, providing the structural basis for non-competitive P2X3 inhibitors.

    Evidence X-ray crystallography, computational modeling, functional mutagenesis (AF-353, AF-219)

    PMID:29674445

    Open questions at the time
    • Whether all allosteric antagonists share identical residue contacts not fully resolved
  16. 2019 High

    Defined a divalent-ion acidic chamber that enables activation by ATP-divalent complexes and prolongs desensitization recovery, identifying a key intrinsic brake on channel activity.

    Evidence X-ray crystallography, MD simulations, patch-clamp, mutagenesis

    PMID:31232692

    Open questions at the time
    • Physiological divalent concentrations governing this in vivo not measured
    • Interplay with raft lipids not addressed
  17. 2019 Medium

    Characterized therapeutically relevant allosteric antagonists (gefapixant/MK-7264 and aurintricarboxylic acid) as state-dependent, non-competitive blockers acting at the negative allosteric site.

    Evidence Patch-clamp on 1321N1/oocytes/DRG, radioligand binding, docking, mutagenesis

    PMID:30927255 PMID:31461640

    Open questions at the time
    • Subunit selectivity (P2X3 vs P2X2/3) of state-dependence not fully resolved
    • Single-lab kinetic characterizations
  18. 2015 High

    Identified Pirt as a direct inhibitory partner binding the P2X3 N-terminus, and showed a Pirt-derived peptide suppresses P2X3 in vivo, revealing an endogenous brake and a peptide-based therapeutic strategy.

    Evidence Co-IP, co-localization, heterologous expression, patch-clamp, in vivo bladder assay

    PMID:26151598

    Open questions at the time
    • Structural basis of N-terminal Pirt binding not resolved
    • Whether Pirt alters trafficking or gating not separated
  19. 2018 High

    Demonstrated direct physical and functional coupling between ASIC3 and P2X3 in a multiprotein complex, with proton-dependent ASIC3 activation cross-inhibiting P2X3.

    Evidence Co-IP, BN-PAGE/SDS-PAGE, patch-clamp, calcium manipulation

    PMID:29636447

    Open questions at the time
    • Stoichiometry/architecture of the ASIC3-P2X3 complex not solved
    • Proposed ion-permeability switch mechanism not structurally confirmed
  20. 2012 Medium

    Established functional crosstalk to TRPV1, with P2X3 activation phosphorylating TRPV1 serines to drive TRPV1-dependent mechanical hyperalgesia.

    Evidence In vivo behavior, Ca2+ imaging, phosphorylation analysis, pharmacology in trigeminal cultures

    PMID:23201260

    Open questions at the time
    • Kinase linking P2X3 Ca2+ influx to TRPV1 phosphorylation not identified
    • Direct vs indirect physical coupling not distinguished
  21. 2021 High

    Identified GPR151 as a direct partner that promotes P2X3 functional activity and pain behavior, linking an orphan GPCR to purinergic nociception.

    Evidence Conditional knockout, overexpression, co-IP, calcium imaging in DRG neurons

    PMID:34244727

    Open questions at the time
    • Whether GPR151 acts on trafficking, gating, or both not resolved
    • GPR151 ligand/signaling input not defined
  22. 2009 Medium

    Provided a state- and subunit-dependent antibody (12D4) modulator, showing P2X3 can be inhibited (homomer, desensitized state) or potentiated (heteromer) and internalized with prolonged exposure.

    Evidence Patch-clamp, antibody-induced internalization assay, in vivo pain models

    PMID:27129281

    Open questions at the time
    • Epitope and structural basis of state preference not mapped
    • Mechanism of internalization not defined
  23. 2013 Medium

    Multiple signaling inputs converge to sensitize or suppress P2X3-mediated nociception — Substance P/NK-1 sensitization, P2X3→PKCε priming, and 17β-estradiol/ERα-GPR30 cAMP-PKA-ERK inhibition.

    Evidence Patch-clamp, Ca2+ imaging, behavioral testing, PKCε translocation assays, ER knockout mice

    PMID:20651096 PMID:23186588 PMID:23610132

    Open questions at the time
    • Direct molecular targets of these pathways on P2X3 not mapped
    • Single-lab studies per modulator
  24. 2020 Medium

    Linked Wnt5b/Ryk signaling to CaMKII-dependent P2X3 membrane trafficking, connecting developmental morphogen signaling to pain-related surface upregulation.

    Evidence Surface biotinylation/WB, patch-clamp, intrathecal antibody/inhibitor, behavior

    PMID:32979370

    Open questions at the time
    • Whether Wnt5b feeds the same Thr388/caveolin-1 step not directly shown
    • Receptor-level epistasis incomplete
  25. 2011 Medium

    Showed that disease-associated P2X3 dysfunction (diabetic mechanical allodynia) operates through increased membrane expression rather than total protein, tying trafficking control to pathology.

    Evidence DiI labeling, patch-clamp, membrane-fraction Western blot, behavior with antagonists

    PMID:21851615

    Open questions at the time
    • Trafficking signal driving membrane enrichment in diabetes not identified
  26. 2023 Medium

    Demonstrated a peripheral chemoreflex role in disease: P2X3 upregulation in the carotid body drives aberrant chemosensory discharge in heart failure, and its blockade restores autonomic balance and cardiac function.

    Evidence In vivo carotid body discharge recording, antagonist administration, Western blot, cardiac/autonomic assessment (rat)

    PMID:36977675

    Open questions at the time
    • Molecular trigger for carotid-body P2X3 upregulation not defined
    • Translation to human heart failure not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally defined gating/allosteric machinery integrates with the phosphorylation, trafficking, partner-protein, and raft-localization controls into a unified regulatory model — and whether heteromeric P2X2/3 architecture changes these rules — remains unresolved.
  • No structure of heteromeric P2X2/3
  • Integrated model of trafficking + gating + partner regulation absent
  • Mapping of in vivo phosphosites to structural states incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9709957 Sensory Perception 2
Partners
ASIC3CAMK2ACAV1CDK5GPR151P2RX2PIRTTRPV1
Complex memberships
ASIC3-P2X3 complexP2X2/3 heteromeric receptor

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 X-ray crystal structures of human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized, and antagonist-bound/closed states revealed the gating cycle, an intracellular 'cytoplasmic cap' motif that stabilizes the open state and creates lateral phospholipid-lined cytoplasmic fenestrations for ion egress, and the binding interactions responsible for competitive inhibition by TNP-ATP and A-317491. X-ray crystallography of human P2X3 receptor in multiple conformational states Nature High 27626375
2018 A negative allosteric site on P2X3 receptors was identified, formed by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Allosteric inhibitors AF-353 and AF-219 bind this site and modulate ATP activation through conformational changes in these domains, as demonstrated by X-ray crystallography, computational modeling, and functional studies of channel mutants. X-ray crystallography combined with computational modeling and functional mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 29674445
2019 Structural and functional studies showed that human P2X3 receptors contain an acidic chamber near the nucleotide-binding pocket that accommodates divalent ions (Ca2+, Mg2+) in two distinct modes depending on nucleotide presence. Divalent ion engagement with the γ-phosphate of ATP enables channel activation by ATP-divalent complexes and cooperatively slows ATP unbinding, prolonging desensitization recovery — a key mechanism limiting channel activity. X-ray crystallography, molecular dynamics simulations, patch-clamp electrophysiology, and mutagenesis eLife High 31232692
1997 P2X2 and P2X3 subunits directly assemble into heteromeric channels with distinct agonist sensitivity and desensitization properties compared to homomers, as demonstrated by cross-immunoprecipitation of differentially epitope-tagged subunits co-expressed in baculovirus-infected insect cells. Baculovirus co-expression with epitope tags, cross-immunoprecipitation, whole-cell electrophysiology The Journal of neuroscience High 9254665
2019 MK-7264 (gefapixant) is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors, exhibiting concentration- and state-dependent block with faster inhibition and greater potency when applied before agonist (preferential activity at closed/resting channels) compared to application during agonist. Whole-cell patch-clamp electrophysiology of 1321N1 cells expressing human P2X3 and P2X2/3 British journal of pharmacology Medium 30927255
2010 AF-353 inhibits P2X3 and P2X2/3 receptors in a non-competitive (allosteric) fashion, as shown by competition binding and intracellular calcium flux experiments, distinguishing it from competitive antagonists A-317491 and TNP-ATP. Radioligand binding, intracellular calcium flux, whole-cell voltage-clamp electrophysiology British journal of pharmacology Medium 20590629
2004 P2X3 receptor localizes into lipid raft membrane microdomains in neurons, as demonstrated biochemically by resistance to cold detergent extraction, solubility after cholesterol depletion with saponin or methyl-β-cyclodextrin, and co-fractionation with low-density sucrose gradient fractions in both cerebellar granule neurons and DRG extracts. Detergent-resistant membrane fractionation, sucrose gradient centrifugation, cholesterol depletion assays Journal of neuroscience research Medium 15139024
2011 In a familial hemiplegic migraine knock-in mouse model, P2X3 receptors are enriched in lipid raft fractions of trigeminal neurons; disruption of lipid rafts by cholesterol depletion removes P2X3 from raft compartments, reduces current amplitude, accelerates current decay, and delays recovery from desensitization, demonstrating that lipid raft localization sustains P2X3 functional potentiation. Sucrose gradient fractionation, whole-cell patch-clamp electrophysiology, kinetic modeling, pharmacological cholesterol depletion Molecular pain Medium 21958474
2007 Activation of metabotropic P2Y receptors (P2Y1,12,13) inhibits P2X3 receptor currents via G protein-dependent facilitation of P2X3 desensitization and suppression of recovery from desensitization. Blocking G proteins with intracellular GDP-β-S abolished this cross-inhibition, establishing a G protein-mediated cross-talk mechanism. Whole-cell patch-clamp on HEK293-hP2X3 cells and rat DRG neurons with intracellular GDP-β-S British journal of pharmacology Medium 17351651
2005 Ecto-protein kinase C phosphorylates extracellular Thr-134 (PKC2) and Ser-178 (PKC3) residues in the P2X3 receptor ectodomain, potentiating alpha,beta-meATP-induced currents; Ala substitution at these sites abolished potentiation and depressed maximum current amplitude without altering EC50. This identifies ecto-PKC phosphorylation as a mechanism for upregulating P2X3 activity. Whole-cell patch-clamp, site-directed mutagenesis, molecular simulation The Journal of neuroscience Medium 16120774
2006 PKC activation enhances ATP-mediated Ca2+ signals (~2.5-fold) and cation currents (~8.5-fold) through P2X3 receptors in transfected cells, but metabolic labeling and in vitro phosphorylation assays showed no direct incorporation of 32PO4 into P2X3 receptor protein, indicating PKC regulation is not via direct receptor phosphorylation. Whole-cell patch-clamp, calcium imaging, metabolic 32P labeling, in vitro kinase assay, immunoprecipitation Biochimica et biophysica acta Medium 17052768
2009 Cdk5, activated by its co-factor p35, phosphorylates the P2X3 receptor on serine residues and downregulates receptor-mediated currents (reduced amplitude without altering desensitization or recovery kinetics), as shown in HEK cells co-transfected with P2X3, Cdk5, and p35. Co-transfection in HEK cells, whole-cell patch-clamp, immunoprecipitation/phosphorylation assay Cellular and molecular neurobiology Medium 19960242
2008 CGRP activates CaMKII in trigeminal neurons, which translocates to the perimembrane region, phosphorylates CREB, triggers nuclear translocation of CREB, and increases P2X3 receptor transcription. This transcriptional upregulation is partly mediated by BDNF acting as an intermediate, since blocking BDNF with antibodies reduced the effect and exogenous BDNF mimicked it. Dominant-negative CREB prevented CGRP-evoked P2X3 upregulation. Immunocytochemistry, dominant-negative CREB transfection, anti-BDNF antibody blockade, gene expression analysis in trigeminal ganglion culture The Journal of biological chemistry High 18460469
2009 Phosphoinositides PIP2 and PIP3 regulate P2X3 function: PIP2 application reverses PI4K inhibitor (wortmannin)-induced depression of P2X3 currents in DRG neurons and recombinant systems. However, a lipid-binding assay showed no direct binding between the P2X3 C-terminus and phosphoinositides (unlike P2X2), indicating an indirect regulatory mechanism for P2X3. Patch-clamp electrophysiology (Xenopus oocytes, HEK293, DRG neurons), wortmannin inhibition, intracellular PIP2 application, lipid-binding assay Molecular pain Medium 19671169
2014 ATP-induced P2X3 receptor activation triggers Ca2+ influx that activates CaMKIIα; CaMKIIα binds the N-terminus of P2X3 and phosphorylates Thr388 in the C-terminus; Thr388 phosphorylation increases P2X3 binding to caveolin-1; and caveolin-1 knockdown abolishes agonist-induced membrane insertion of P2X3. This CaMKIIα/caveolin-1 pathway drives ligand-induced membrane delivery of P2X3. Co-immunoprecipitation, site-directed mutagenesis, caveolin-1 knockdown, confocal imaging, surface biotinylation in HEK293T and primary sensory neurons Journal of molecular cell biology High 24755854
2021 GPR151 couples with P2X3 ion channels in nociceptive DRG neurons and promotes P2X3 functional activity. Knockout of GPR151 suppressed P2X3-mediated calcium elevation and spontaneous pain behavior; overexpression of GPR151 enhanced P2X3-mediated calcium elevation and DRG excitability. Co-immunoprecipitation confirmed physical interaction between GPR151 and P2X3. Conditional knockout, overexpression, co-immunoprecipitation, calcium imaging in DRG neurons Brain High 34244727
2015 Pirt interacts with P2X3 through its N-terminal 14 amino-acid residues; Pirt co-localizes with P2X3 in bladder nerve fibers; heterologous Pirt expression significantly reduces P2X3-mediated currents; and a TAT-conjugated Pirt N14 peptide inhibits P2X3 activation and alleviates bladder overactivity in vivo. Co-immunoprecipitation, co-localization (immunofluorescence), heterologous expression, patch-clamp electrophysiology, in vivo bladder function assay Nature communications High 26151598
2018 ASIC3 and P2X3 receptors physically associate to form a multiprotein complex (confirmed by co-immunoprecipitation and BN-PAGE/SDS-PAGE analysis), and ASIC3 stimulation strongly inhibits P2X3 receptor current partly through a Ca2+-dependent mechanism; the proton-binding site of ASIC3 is critical for this inhibitory effect, and the two receptors appear to switch ionic permeabilities during activation. Co-immunoprecipitation, BN-PAGE/SDS-PAGE, patch-clamp electrophysiology, calcium manipulation Nature communications High 29636447
2012 P2X3 activation by αβmeATP in trigeminal sensory neurons phosphorylates serine residues (but not threonine) in TRPV1, and this P2X3-induced TRPV1 phosphorylation is required for the observed TRPV1-dependent mechanical hyperalgesia; blocking TRPV1 with AMG9810 prevented αβmeATP-induced hyperalgesia. Ca2+ transients induced by capsaicin were amplified following P2X3 activation in co-expressing neurons. In vivo behavioral testing, Ca2+ imaging, immunoprecipitation/phosphorylation analysis, pharmacological antagonism in trigeminal ganglion cultures Neuroscience Medium 23201260
2009 Monoclonal antibody 12D4 against human P2X3 binds the inactivated (desensitized) state to inhibit homomeric P2X3 with IC50 ~16 nM; conversely, short-term 12D4 application potentiates heteromeric P2X2/3 currents. Prolonged (~20 h) antibody exposure causes internalization of both homomeric and heteromeric receptors from the plasma membrane, providing a distinct state-dependent and subunit-composition-dependent mechanism of P2X3 modulation. Patch-clamp electrophysiology, antibody-induced receptor internalization assay, in vivo pain models The Journal of biological chemistry Medium 27129281
2013 Substance P sensitizes P2X3 receptors through activation of the NK-1 receptor in nociceptive trigeminal neurons: NK-1 co-expressed with P2X3, and NK-1 agonists significantly potentiated αβmeATP-induced currents and Ca2+ responses in a manner completely blocked by NK-1 antagonist GR82334. Single-cell RT-PCR, immunohistochemistry, Ca2+ imaging, whole-cell patch-clamp in trigeminal neurons Journal of dental research Medium 20651096
2011 Enhanced membrane expression of P2X3 receptors (without change in total P2X3 protein) contributes to mechanical allodynia in STZ-induced diabetic rats; ATP-activated P2X3 currents were ~2-fold larger in labeled DRG neurons from diabetic rats, while peripheral P2X3 antagonists reversed allodynia. DiI retrograde labeling, whole-cell patch-clamp, Western blot of membrane fractions, behavioral testing with P2X receptor antagonists Molecular pain Medium 21851615
2020 Wnt5b/Ryk signaling promotes CaMKII-dependent membrane trafficking of P2X3 receptors in DRG neurons: Wnt5b application enhanced membrane P2X3 protein and αβmeATP-induced currents; anti-Ryk antibody or CaMKII inhibitor KN93 prevented Wnt5b-induced P2X3 membrane upregulation and pain hypersensitivity. Surface biotinylation/Western blot, patch-clamp electrophysiology, in vivo intrathecal injection with antibody/inhibitor, behavioral testing Experimental neurology Medium 32979370
2013 Neuronal P2X3 receptor activation increases PKCε translocation to the cell membrane in DRG neurons; pharmacological blockade of PKCε translocation prevented P2X3-dependent sensitization to sub-threshold PGE2. This establishes a P2X3 → PKCε pathway that enables sensitization of nociceptors to inflammatory mediators. In vivo paw injection of agonists/antagonists, Western blot for PKCε membrane translocation, periganglionar antisense knockdown Neuropharmacology Medium 23186588
2013 17β-estradiol rapidly inhibits P2X3 receptor-mediated pain through ERα and GPR30 (but not ERβ) receptors expressed in DRG neurons via a cAMP-PKA-ERK1/2 intracellular pathway; ERK inhibitors reversed E2's inhibitory effect on P2X3 currents, and E2 lacked effect in ERα-knockout mice. Behavioral pain testing, whole-cell patch-clamp in DRG neurons, ERα/ERβ knockout mice, pharmacological pathway inhibition Endocrinology Medium 23610132
2019 Aurintricarboxylic acid (ATA) is a nanomolar allosteric antagonist of P2X3 (IC50 72.9 nM for rP2X3); radioligand binding showed ATA does not compete with [3H]-ATP, confirming non-competitive mechanism. Molecular docking and site-directed mutagenesis identified the negative allosteric site on hP2X3 as the binding location. Two-electrode voltage clamp (Xenopus oocytes), patch-clamp (mouse DRG), radioligand binding, site-directed mutagenesis, molecular docking Neuropharmacology Medium 31461640
2023 P2X3 receptors are upregulated two-fold in carotid body peripheral chemosensory afferents during heart failure; pharmacological P2X3 antagonism abolished spontaneous episodic burst discharges from the carotid body, normalized chemoreceptor sensitivity and breathing pattern, reinstated autonomic balance, and improved cardiac function in a rat model. In vivo electrophysiology (carotid body discharge recording), P2X3 receptor antagonist administration, Western blot, autonomic and cardiac functional assessment Nature communications Medium 36977675
1997 The mouse P2X3 gene consists of 12 exons spanning ~40 kb, has multiple transcription initiation sites 162-168 bp upstream of the translation start codon, lacks TATA/CCAAT boxes or initiator elements, and maps to chromosome 2p by FISH. Genomic library screening, RNase protection, primer extension, fluorescence in situ hybridization (FISH) Gene Medium 9300827
1998 After sciatic nerve axotomy, P2X3 receptor expression decreased by >50% in L4/5 DRG neurons; intrathecal delivery of GDNF completely reversed this axotomy-induced downregulation, establishing GDNF as a regulator of P2X3 expression in nociceptive sensory neurons. Immunohistochemistry with polyclonal antibody, intrathecal GDNF infusion, quantitative cell counting Molecular and cellular neurosciences Medium 9828090
1998 P2X3 receptor immunoreactivity is localized ultrastructurally to endoplasmic reticulum and Golgi apparatus in trigeminal ganglion soma, and to presynaptic core terminals in synaptic glomeruli of lamina II of the dorsal horn that are postsynaptic to unlabeled vesicle-containing dendrites and axons, identifying sites of presynaptic ATP release for sensory signaling. Electron microscopy immunocytochemistry with selective IgG antibodies Neuroreport Medium 9721930
2001 P2X2 and P2X3 subunits are co-expressed in hypoxia-responsive petrosal neurons forming functional chemosensory units with carotid body receptor clusters. ATP acts as a co-transmitter in chemosensory signaling, with P2X2-P2X3 receptor activation contributing to the hypoxic and hypercapnic responses; co-localization of P2X2 and P2X3 protein was confirmed at CB afferent terminals. RT-PCR, single-cell RT-PCR, electrophysiology of co-cultures, confocal immunofluorescence, suramin blockade The Journal of physiology Medium 11744746

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Molecular and cellular neurosciences 388 9828090
2022 Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet (London, England) 253 35248186
2016 X-ray structures define human P2X(3) receptor gating cycle and antagonist action. Nature 213 27626375
2003 P2X3 receptors and peripheral pain mechanisms. The Journal of physiology 166 12832496
2007 P2X3 receptor involvement in pain states. Molecular neurobiology 159 17952660
2001 Expression of P2X2 and P2X3 receptor subunits in rat carotid body afferent neurones: role in chemosensory signalling. The Journal of physiology 133 11744746
2010 AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. British journal of pharmacology 106 20590629
2010 Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain : a journal of neurology 106 20802203
1998 Ultrastructural localization of P2X3 receptors in rat sensory neurons. Neuroreport 100 9721930
1997 Baculovirus expression provides direct evidence for heteromeric assembly of P2X2 and P2X3 receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 99 9254665
2006 Localization of P2X2 and P2X3 receptors in rat trigeminal ganglion neurons. Neuroscience 93 17110047
2008 Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. The Journal of biological chemistry 89 18460469
2003 Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert opinion on therapeutic targets 89 12885270
2018 Druggable negative allosteric site of P2X3 receptors. Proceedings of the National Academy of Sciences of the United States of America 88 29674445
2019 BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulmonary pharmacology & therapeutics 81 30902655
2019 Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation. British journal of pharmacology 81 30927255
2021 GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation. Brain : a journal of neurology 77 34244727
2019 Electroacupuncture Stimulation Alleviates CFA-Induced Inflammatory Pain Via Suppressing P2X3 Expression. International journal of molecular sciences 72 31269659
2011 Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Molecular pain 67 21851615
2003 Capsaicin receptor VR1 and ATP purinoceptor P2X3 in painful and nonpainful human tooth pulp. Journal of orofacial pain 67 14520770
2004 P2X2 and P2X3 purinoceptors in the rat enteric nervous system. Histochemistry and cell biology 61 14767775
2013 ATP P2X3 receptors and neuronal sensitization. Frontiers in cellular neuroscience 60 24363643
2015 Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome. Purinergic signalling 59 25809868
2004 P2X3 receptor localizes into lipid rafts in neuronal cells. Journal of neuroscience research 56 15139024
2012 Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. Neuropharmacology 51 23186588
2008 Expression of P2X3 receptor in the trigeminal sensory nuclei of the rat. The Journal of comparative neurology 50 18067147
2004 VR1-, VRL-1- and P2X3 receptor-immunoreactive innervation of the rat temporomandibular joint. Brain research 50 15081392
2012 P2X₃ and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons. Neuroscience 48 23201260
2007 Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. British journal of pharmacology 48 17351651
2018 The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel. Nature communications 47 29636447
2003 Intraganglionic laminar endings in the rat esophagus contain purinergic P2X2 and P2X3 receptor immunoreactivity. Anatomy and embryology 47 14624359
2017 P2X3 receptor involvement in endometriosis pain via ERK signaling pathway. PloS one 45 28898282
2013 17β-estradiol rapidly attenuates P2X3 receptor-mediated peripheral pain signal transduction via ERα and GPR30. Endocrinology 45 23610132
2012 Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-α and estrogen receptor-β knockout mice. Neuroreport 45 22581043
2009 Double P2X2/P2X3 purinergic receptor knockout mice do not taste NaCl or the artificial sweetener SC45647. Chemical senses 45 19833661
2021 Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome. Journal of dental sciences 44 35028015
2019 Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. eLife 44 31232692
2005 Developmentally regulated expression of the P2X3 receptor in the mouse cochlea. Histochemistry and cell biology 43 16341871
2004 The co-expression of P2X3 receptor with VR1 and VRL-1 in the rat trigeminal ganglion. Brain research 43 14725976
2021 Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers. Scientific reports 42 34615939
2012 P2X3-mediated peripheral sensitization of neuropathic pain in resiniferatoxin-induced neuropathy. Experimental neurology 42 22391132
2020 P2X3-Receptor Antagonists as Potential Antitussives: Summary of Current Clinical Trials in Chronic Cough. Lung 41 32661659
2006 Selective labeling of central and peripheral sensory neurons in the developing zebrafish using P2X(3) receptor subunit transgenes. Neuroscience 41 16413125
2009 Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors. Molecular pain 39 19671169
2008 Behavioural responses and expression of P2X3 receptor in trigeminal ganglion after experimental tooth movement in rats. Archives of oral biology 39 18945422
2007 Neuronal expression of P2X3 purinoceptors in the rat retina. Neuroscience 39 17367943
2005 Regulation of human recombinant P2X3 receptors by ecto-protein kinase C. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 16120774
2015 P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients. Oncotarget 38 26517690
2000 P2X3 receptor in injured human sensory neurons. Neuroreport 38 10790870
2010 P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex. Journal of applied physiology (Bethesda, Md. : 1985) 37 20798273
2019 Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain. International journal of molecular sciences 36 30609840
2014 Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators. Neuroscience 36 25446353
2008 Homomeric and heteromeric P2X3 receptors in peripheral sensory neurons. Current opinion in investigational drugs (London, England : 2000) 36 18600577
2005 P2X2 and P2X3 receptor expression in postnatal and adult rat urinary bladder and lumbosacral spinal cord. American journal of physiology. Regulatory, integrative and comparative physiology 36 15947072
2000 Embryonic expression of a P2X(3) receptor encoding gene in zebrafish. Mechanisms of development 36 11091083
2013 Desensitization properties of P2X3 receptors shaping pain signaling. Frontiers in cellular neuroscience 35 24367291
2012 Interaction between P2X3 and oestrogen receptor (ER)α/ERβ in ATP-mediated calcium signalling in mice sensory neurones. Journal of neuroendocrinology 35 22175770
2010 Substance P sensitizes P2X3 in nociceptive trigeminal neurons. Journal of dental research 34 20651096
2011 Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Molecular pain 33 21958474
2010 P2X3 and P2X2/3 receptors mediate mechanical hyperalgesia induced by bradykinin, but not by pro-inflammatory cytokines, PGE₂ or dopamine. European journal of pharmacology 32 20868656
2019 Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications. Expert opinion on therapeutic patents 31 31726893
2006 Protein kinase C regulation of P2X3 receptors is unlikely to involve direct receptor phosphorylation. Biochimica et biophysica acta 31 17052768
2019 Update on the clinical development of gefapixant, a P2X3 receptor antagonist for the treatment of refractory chronic cough. Pulmonary pharmacology & therapeutics 30 30880151
2016 Modulation of P2X3 and P2X2/3 Receptors by Monoclonal Antibodies. The Journal of biological chemistry 30 27129281
2015 Morphology of P2X3-immunoreactive nerve endings in the rat laryngeal mucosa. Histochemistry and cell biology 30 26475709
2013 Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization. American journal of physiology. Gastrointestinal and liver physiology 30 23989007
2008 Role of P2X3 receptor in myocardial ischemia injury and nociceptive sensory transmission. Autonomic neuroscience : basic & clinical 28 18276198
2019 Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors. Neuropharmacology 27 31461640
2008 Expressions of P2X2 and P2X3 receptors in rat nodose neurons after myocardial ischemia injury. Autonomic neuroscience : basic & clinical 27 19064335
2022 Association between P2X3 receptors and neuropathic pain: As a potential therapeutic target for therapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 35489283
2020 Wnt5b/Ryk-mediated membrane trafficking of P2X3 receptors contributes to bone cancer pain. Experimental neurology 26 32979370
2014 Comparative analysis of P2X1, P2X2, P2X3, and P2X4 receptor subunits in rat nodose ganglion neurons. PloS one 25 24798490
2009 The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation. Cellular and molecular neurobiology 25 19960242
2002 Expression of adenosine triphosphate P2X3 receptors in rat molar pulp and trigeminal ganglia. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 25 12424458
2023 P2X3 receptor antagonism attenuates the progression of heart failure. Nature communications 24 36977675
2023 The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial. Respiratory research 24 37041539
2017 Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors. ACS chemical neuroscience 24 28323403
2016 Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats. Purinergic signalling 24 27817132
2009 Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats. Histochemistry and cell biology 24 19784665
2007 Alpha1-adrenergic receptors augment P2X3 receptor-mediated nociceptive responses in the uninjured state. The journal of pain 24 17512257
2019 Electroacupuncture downregulates P2X3 receptor expression in dorsal root ganglia of the spinal nerve-ligated rat. Molecular pain 23 30983496
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
2020 Activation of ATF3/AP-1 signaling pathway is required for P2X3-induced endometriosis pain. Human reproduction (Oxford, England) 22 32303740
2009 Expression of P2X3 purinoceptors in suburothelial myofibroblasts of the normal human urinary bladder. International journal of urology : official journal of the Japanese Urological Association 22 19456993
2022 Treatment of chronic cough: P2X3 receptor antagonists and beyond. Pharmacology & therapeutics 21 35263649
2020 Electroacupuncture alleviates diabetic neuropathic pain in rats by suppressing P2X3 receptor expression in dorsal root ganglia. Purinergic signalling 21 33011961
2019 Role of hesperidin in P2X3 receptor-mediated neuropathic pain in the dorsal root ganglia. The International journal of neuroscience 21 30621504
2018 Microencapsulated Schwann cell transplantation inhibits P2X3 receptor expression in dorsal root ganglia and neuropathic pain. Neural regeneration research 21 30233070
2014 Distribution of TRPVs, P2X3, and parvalbumin in the human nodose ganglion. Cellular and molecular neurobiology 21 24764033
2001 Heterogeneity of the functional expression of P2X3 and P2X2/3 receptors in the primary nociceptive neurons of rat. Neurochemical research 21 11699951
2015 Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3. Nature communications 20 26151598
2002 P2X(3) receptor expression at early stage of mouse embryogenesis. Mechanisms of development 20 12351197
2024 Benefit-Risk Profile of P2X3 Receptor Antagonists for Treatment of Chronic Cough: Dose-Response Model-Based Network Meta-Analysis. Chest 19 38857780
2023 Role of ATP in migraine mechanisms: focus on P2X3 receptors. The journal of headache and pain 19 36597043
2022 First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics. British journal of clinical pharmacology 19 35437837
2012 Regulation of P2X3 receptor structure and function. CNS & neurological disorders drug targets 19 22963434
2006 Expression of ATP-gated P2X3 receptors in rat gustatory papillae and taste buds. Archives of histology and cytology 19 17287582
1997 Structure and chromosomal mapping of the mouse P2X3 gene. Gene 19 9300827
2022 Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study. Clinical pharmacokinetics 18 35624408
2014 CaMKIIα and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor. Journal of molecular cell biology 18 24755854

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