Affinage

P2RX3

P2X purinoceptor 3 · UniProt P56373

Length
397 aa
Mass
44.3 kDa
Annotated
2026-04-29
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RX3 encodes P2X3, a trimeric ATP-gated cation channel selectively expressed in sensory neurons that mediates rapidly desensitizing purinergic currents as a homomeric (P2X3)₃ channel or, together with P2X2, as a heteromeric P2X2/3 channel with distinct kinetics (PMID:7566120, PMID:9254665). X-ray crystallography has resolved the full gating cycle—resting, open, and desensitized states—revealing an intracellular cytoplasmic cap that stabilizes the open pore, an acidic chamber that coordinates divalent cation–ATP complexes to control recovery from desensitization, and a negative allosteric site (LF/DF/LB domains) targeted by clinically developed antagonists including gefapixant (PMID:27626375, PMID:29674445, PMID:31232692, PMID:30927255). Channel activity is post-translationally tuned by calcineurin-mediated dephosphorylation of N-terminal residues governing desensitization, ecto-PKC phosphorylation of extracellular T134/S178, Cdk5-dependent serine phosphorylation, PIP2 levels regulated by P2Y receptors via PLC, lipid-raft compartmentalization, and membrane trafficking driven by CGRP/PKA, NGF/PKC, and Wnt5b/CaMKII pathways (PMID:9175092, PMID:16120774, PMID:19960242, PMID:23249537, PMID:21958474, PMID:18459072, PMID:32979370). Physical partners Pirt (endogenous inhibitor via its N-terminal 14 residues), ASIC3 (inhibitory complex formation), and GPR151 (positive modulator upstream of a nociceptor-to-CNS cascade) directly regulate P2X3 signaling in nociceptive and visceral sensory circuits (PMID:26151598, PMID:29636447, PMID:34244727).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Cloning P2X3 from DRG and demonstrating that P2X2/P2X3 co-expression reconstitutes native sensory neuron ATP currents established that P2X3 forms both homomeric and heteromeric ligand-gated channels with distinct pharmacological profiles.

    Evidence cDNA cloning from rat DRG; heterologous expression in Xenopus oocytes with electrophysiology

    PMID:7566120

    Open questions at the time
    • stoichiometry of heteromeric P2X2/3 channels not determined
    • no structural information available
  2. 1997 High

    Biochemical demonstration of P2X2–P2X3 physical co-assembly by co-immunoprecipitation, together with the discovery that calcineurin-mediated dephosphorylation of N-terminal residues controls P2X3 desensitization, defined both subunit assembly and the first post-translational regulatory mechanism.

    Evidence Baculovirus co-expression with cross-IP; oocyte electrophysiology with calcineurin inhibitors, autoinhibitory peptide injection, and N-terminal truncation mutagenesis

    PMID:9175092 PMID:9254665

    Open questions at the time
    • specific N-terminal phosphorylation sites not identified
    • calcineurin recruitment mechanism unknown
  3. 2000 High

    Genetic ablation of P2X3 proved it is the obligate subunit for rapidly desensitizing ATP currents in DRG neurons and for heteromeric P2X2/3 responses in nodose ganglia, establishing its non-redundant role in peripheral sensory transduction.

    Evidence P2X3 knockout mouse; patch-clamp in DRG and nodose neurons; behavioral nociception testing

    PMID:11069182

    Open questions at the time
    • compensatory changes in other P2X family members not fully assessed
    • central versus peripheral contributions to pain phenotype not separated
  4. 2005 High

    Identification of ecto-PKC phosphorylation of extracellular T134/S178 and P2Y1-mediated Gαq/11 inhibition of P2X3 revealed that the channel is regulated on both faces of the membrane—extracellularly by kinase activity and intracellularly by metabotropic receptor crosstalk.

    Evidence Site-directed mutagenesis and patch clamp in HEK293 cells; pharmacological pathway dissection with P2Y1 agonists/antagonists and GDP-βS in DRG neurons

    PMID:16120774 PMID:16181623

    Open questions at the time
    • identity of the endogenous ecto-PKC isoform in vivo unclear
    • structural basis for extracellular phosphorylation-induced potentiation unknown
  5. 2007 Medium

    Demonstrating that multiple P2Y receptors (P2Y1/12/13) accelerate P2X3 desensitization and slow recovery via G-protein signaling established that co-released ATP can simultaneously activate and brake P2X3, providing a homeostatic feedback mechanism.

    Evidence Patch clamp in HEK293-hP2X3 cells and rat DRG neurons with intracellular GDP-βS perfusion and selective receptor pharmacology

    PMID:17351651

    Open questions at the time
    • specific G-protein effector downstream of P2Y12/13 acting on P2X3 not identified
    • in vivo relevance of simultaneous P2Y/P2X3 co-activation not tested
  6. 2009 Medium

    Discovery that PIP2 sustains P2X3 current amplitude and recovery from desensitization—indirectly, without direct C-terminal lipid binding—and that Cdk5/p35 phosphorylation suppresses P2X3 currents added two further layers of post-translational control: lipid environment and cell-cycle kinase activity.

    Evidence Patch clamp with wortmannin and exogenous PIP2 rescue across DRG/oocytes/HEK cells; lipid-binding assay; HEK co-transfection of P2X3 with Cdk5/p35 and phosphoserine immunoprecipitation

    PMID:19671169 PMID:19960242

    Open questions at the time
    • mechanism of indirect PIP2 sensing unknown
    • specific Cdk5 phosphorylation sites on P2X3 not mapped
    • in vivo Cdk5/p35 relevance untested
  7. 2011 Medium

    Findings that pathological P2X3 upregulation in diabetic neuropathy occurs via enhanced membrane trafficking rather than total protein increase, and that lipid-raft localization sustains P2X3 potentiation, established surface trafficking and membrane microdomain partitioning as key determinants of channel availability in disease.

    Evidence Plasma membrane fractionation and western blot in STZ-diabetic DRG neurons; lipid raft isolation and cholesterol depletion with electrophysiology in CaV2.1 knock-in migraine model neurons

    PMID:21851615 PMID:21958474

    Open questions at the time
    • trafficking machinery mediating P2X3 membrane insertion not identified
    • whether raft localization mechanism is direct or via interacting proteins unknown
  8. 2012 Medium

    P2Y2 receptor activation was shown to inhibit homomeric P2X3 specifically via PLC-mediated PIP2 depletion (rescued by exogenous PIP2), completing the mechanistic link between metabotropic purinergic signaling and P2X3 lipid regulation, while P2X3–TRPV1 cross-sensitization via phosphorylation was identified in trigeminal neurons.

    Evidence Patch clamp in DRG with PLC inhibitor and PIP2 rescue; behavioral hyperalgesia, Ca²⁺ imaging, and TRPV1 phospho-serine western blot in trigeminal neurons

    PMID:23201260 PMID:23249537

    Open questions at the time
    • identity of kinase phosphorylating TRPV1 downstream of P2X3 unknown
    • whether P2X3–TRPV1 form a direct physical complex not tested
  9. 2015 High

    Identification of Pirt as a direct physical inhibitor of P2X3 via its N-terminal 14 residues—validated by KO, heterologous reconstitution, and peptide rescue of bladder overactivity—established the first endogenous protein inhibitor of P2X3, while NF-κB-driven transcriptional upregulation through promoter demethylation was defined as a mechanism in diabetic neuropathy.

    Evidence Pirt-KO mouse; Co-IP; TAT-Pirt(N14) peptide rescue of bladder function; ChIP/bisulfite sequencing of P2X3 promoter with lentiviral p65-siRNA in STZ rats

    PMID:26130762 PMID:26151598

    Open questions at the time
    • stoichiometry of Pirt–P2X3 interaction not determined
    • whether Pirt modulates heteromeric P2X2/3 unknown
    • epigenetic regulation in non-diabetic pain states not assessed
  10. 2016 High

    X-ray crystal structures of human P2X3 in four conformational states resolved the full gating cycle, revealing the cytoplasmic cap that forms phospholipid-lined lateral fenestrations for ion exit and showing how competitive antagonists stabilize the resting state—transforming mechanistic understanding from pharmacology to atomic-resolution structural biology.

    Evidence X-ray crystallography of apo, agonist-bound open, agonist-bound desensitized, and antagonist-bound P2X3

    PMID:27626375

    Open questions at the time
    • no cryo-EM structure in lipid bilayer context
    • structural basis of desensitization-to-resting transition not fully captured
  11. 2018 High

    Structural identification of a negative allosteric site (LF/DF/LB domains) bound by clinically relevant antagonists (AF-353, AF-219/gefapixant), together with discovery of the inhibitory ASIC3–P2X3 complex, defined two distinct non-competitive mechanisms for suppressing P2X3 activity.

    Evidence X-ray crystallography with allosteric inhibitors plus functional mutagenesis; Co-IP, BN-PAGE, and electrophysiology with ASIC3 proton-binding site mutants

    PMID:29636447 PMID:29674445

    Open questions at the time
    • whether ASIC3–P2X3 complex interface overlaps with allosteric site unknown
    • in vivo pharmacology of allosteric site in chronic pain models limited
  12. 2019 High

    Crystal structures of divalent cation–ATP complexes in the P2X3 acidic chamber explained how Mg²⁺/Ca²⁺ coordination slows ATP unbinding and prolongs desensitization recovery, while state-dependent kinetic analysis of gefapixant confirmed its preferential action on closed/resting channels—refining the pharmacological strategy for allosteric P2X3 blockade.

    Evidence X-ray crystallography with Ca²⁺/Mg²⁺-ATP; MD simulations; mutagenesis; wash-on kinetic electrophysiology in cells expressing P2X3 and P2X2/3

    PMID:30927255 PMID:31232692

    Open questions at the time
    • clinical significance of divalent-dependent recovery kinetics in pathological ATP concentrations not established
    • full structure of P2X2/3 heteromer not determined
  13. 2021 High

    Conditional knockout of GPR151 showed it physically couples with and functionally promotes P2X3-mediated calcium signaling in DRG neurons, and is required for CCI-induced CSF1 upregulation and spinal microglial activation, placing GPR151 as an upstream modulator in a nociceptor-to-CNS inflammatory cascade.

    Evidence Conditional Gpr151 KO; Ca²⁺ imaging; DRG excitability recordings; CSF1 and microglial activation assays; human DRG co-expression confirmed

    PMID:34244727

    Open questions at the time
    • signaling mechanism by which GPR151 enhances P2X3 unknown (direct allosteric vs. second messenger)
    • GPR151 endogenous ligand identity uncertain
  14. 2023 High

    Demonstration that P2X3 is upregulated in carotid body chemosensory afferents in heart failure and that its antagonism rescues disordered breathing, chemoreceptor hyperactivity, autonomic imbalance, and cardiac dysfunction expanded the pathophysiological significance of P2X3 beyond nociception to cardiorespiratory disease.

    Evidence Heart failure rat model; carotid body afferent discharge recording; P2X3 antagonist pharmacology; multi-organ functional outcomes

    PMID:36977675

    Open questions at the time
    • source of elevated ATP in heart-failure carotid body not identified
    • whether P2X3 upregulation is transcriptional or trafficking-mediated not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structure of the heteromeric P2X2/3 channel, the mechanism by which PIP2 indirectly regulates P2X3 without C-terminal binding, the identity of specific Cdk5 phosphorylation sites, the structural basis of the ASIC3–P2X3 inhibitory complex, and how GPR151 mechanistically promotes P2X3 activity.
  • no structure of P2X2/3 heteromer
  • PIP2 sensing mechanism not identified
  • GPR151 coupling mechanism to P2X3 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
GO:0005215 transporter activity 1
Partners
ASIC3CASKGPR151P2RX2PIRTTRPV1
Complex memberships
ASIC3-P2X3 complexP2X2/P2X3 heteromeric channel

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 P2X3 was cloned from rat dorsal root ganglia; coexpression of P2X3 with P2X2 (but not other P2X subunit combinations) reconstituted ATP-gated currents matching those of native sensory neurons, demonstrating heteropolymerization of P2X2 and P2X3 subunits into a novel channel with distinct properties from either homomer. cDNA cloning; heterologous expression in Xenopus oocytes; electrophysiology Nature High 7566120
1997 Direct biochemical evidence that P2X2 and P2X3 subunits physically assemble into heteromeric channels: baculovirus-expressed epitope-tagged P2X2 and P2X3 proteins were cross-immunoprecipitated, and co-infected cells displayed ATP-evoked currents with agonist sensitivity and desensitization kinetics distinct from either homomeric channel. Baculovirus expression; cross-immunoprecipitation with epitope-specific antibodies; whole-cell electrophysiology The Journal of Neuroscience High 9254665
1997 P2X3 desensitization is calcium-dependent and regulated by the phosphatase calcineurin: removal of extracellular calcium or pretreatment with cyclosporin (calcineurin inhibitor) abolished desensitization; injection of calcineurin auto-inhibitory peptide progressively reduced desensitization; truncated P2X3 lacking the N-terminal intracellular region did not desensitize, implicating phosphorylated N-terminal residues as substrates for calcineurin-mediated dephosphorylation. Xenopus oocyte expression; two-electrode voltage clamp; pharmacological inhibition of calcineurin; N-terminal truncation mutagenesis; intracellular peptide injection Neuroreport High 9175092
2000 Genetic ablation of P2X3 in mice eliminated rapidly desensitizing ATP-gated cation currents in DRG neurons; nodose ganglion ATP responses showed altered kinetics and pharmacology consistent with loss of P2X2/3 heteromultimers, confirming that P2X3 is the obligate subunit for both homomeric and heteromeric channel subtypes in sensory neurons. P2X3 gene knockout; patch-clamp electrophysiology in DRG and nodose ganglion neurons; behavioral nociception testing Nature High 11069182
2005 Ecto-protein kinase C (ecto-PKC) potentiates P2X3 receptor activity by phosphorylating specific serine/threonine residues (T134, S178) in the extracellular domain: alanine substitution at these sites abolished UTP-induced potentiation and depressed maximal current amplitude without shifting EC50, establishing a novel extracellular phosphorylation mechanism for P2X3 regulation. Whole-cell patch clamp in HEK293 cells transfected with human P2X3; site-directed mutagenesis of ecto-PKC consensus sites; pharmacological PKC inhibition; molecular modeling The Journal of Neuroscience High 16120774
2005 Metabotropic P2Y1 receptors in rat DRG neurons inhibit P2X3 receptor-mediated currents via G protein activation: the P2Y1 agonist ADP-β-S suppressed α,β-meATP-evoked P2X3 currents, an effect blocked by the G-protein inhibitor GDP-β-S and the P2Y1 antagonist MRS 2179, but not by pertussis toxin, indicating a Gα(q/11)-coupled mechanism. Whole-cell patch clamp in cultured rat DRG neurons; pharmacological dissection with selective agonists/antagonists and GDP-β-S European Journal of Pharmacology Medium 16181623
2007 P2Y1, P2Y12, and P2Y13 receptor activation (via ADP-β-S) G-protein-dependently accelerates desensitization of P2X3 channels and slows recovery from desensitization; blocking G proteins with intracellular GDP-β-S equalized ATP- and α,β-meATP-evoked currents, demonstrating that co-released ATP simultaneously activates inhibitory P2Y receptors that modulate P2X3 kinetics. Whole-cell patch clamp in HEK293-hP2X3 cells and rat DRG neurons; intracellular GDP-β-S perfusion; selective receptor agonists/antagonists British Journal of Pharmacology Medium 17351651
2008 CGRP upregulates P2X3 receptor function in trigeminal neurons via PKA-dependent signaling, enhancing receptor trafficking to the neuronal membrane and activating gene transcription; NGF rapidly and reversibly upregulates P2X3 function via PKC phosphorylation, counteracted by anti-NGF antibodies; the two pathways use distinct mechanisms and time domains. Cultured trigeminal neurons; patch clamp electrophysiology; pharmacological PKA/PKC inhibition; anti-NGF antibody blockade; cell-surface trafficking assays Molecular Neurobiology Medium 18459072
2009 Phosphoinositides (PIP2) regulate homomeric P2X3 channel function: PI4K inhibition by wortmannin dramatically reduced P2X3 current amplitude and slowed recovery from desensitization in DRG neurons; intracellular PIP2 application fully reversed wortmannin-mediated inhibition, whereas the P2X3 C-terminus showed no direct phosphoinositide binding (unlike P2X2), indicating indirect PIP2 sensing. Whole-cell patch clamp in rat DRG neurons, Xenopus oocytes and HEK293 cells; wortmannin PI4K/PI3K inhibition; intracellular PIP2 application; lipid-binding assay with recombinant C-terminal domains Molecular Pain Medium 19671169
2009 Cdk5 kinase, activated by its co-factor p35, downregulates P2X3 receptor function via serine phosphorylation: co-transfection of P2X3 with Cdk5 and p35 in HEK cells increased P2X3 serine phosphorylation and reduced current amplitude without altering desensitization kinetics, identifying Cdk5 as a negative post-translational regulator of P2X3. HEK cell co-transfection; whole-cell patch clamp; phosphoserine immunoprecipitation Cellular and Molecular Neurobiology Medium 19960242
2011 In diabetic neuropathy (STZ model), enhanced P2X3 receptor activity correlates with increased P2X3 protein expression specifically in the plasma membrane fraction (not total expression), indicating that trafficking of P2X3 to the cell surface—rather than total synthesis—underlies enhanced nociceptive signaling. Patch clamp in retrogradely labeled DRG neurons; plasma membrane fractionation and western blot; P2X receptor antagonist behavioral rescue Molecular Pain Medium 21851615
2011 Lipid raft membrane microenvironment controls P2X3 receptor compartmentalization and function: knock-in migraine model neurons had enlarged lipid raft fractions enriched with P2X3 receptors; cholesterol depletion (disrupting rafts) confined P2X3 to non-raft domains, accelerated current decay, and delayed recovery, demonstrating that lipid raft localization sustains P2X3 receptor potentiation. Lipid raft biochemical isolation; whole-cell patch clamp; cholesterol depletion (methyl-β-cyclodextrin); kinetic modeling; Ca(V)2.1 channel blocker pretreatment Molecular Pain Medium 21958474
2012 P2X3 and TRPV1 functionally interact in trigeminal sensory neurons: P2X3 activation by α,β-meATP caused dose-dependent masseter hyperalgesia blocked by a TRPV1 antagonist; P2X3 activation amplified capsaicin-induced Ca2+ transients in co-expressing neurons; P2X3 activation induced phosphorylation of serine residues on TRPV1 in TG cultures, revealing cross-receptor sensitization via phosphorylation. Behavioral mechanosensitivity assay; intramuscular injections; Ca2+ imaging; immunohistochemistry; western blot for serine phosphorylation of TRPV1 Neuroscience Medium 23201260
2012 P2Y2 receptor activation inhibits homomeric P2X3 (but not heteromeric P2X2/3) currents in DRG neurons via PLC-mediated PIP2 depletion: UTP reduced P2X3 peak amplitudes, reversed by exogenous PIP2; immunostaining confirmed P2X3 and P2Y2 co-expression in DRG neurons, establishing P2Y2-PLC-PIP2 as a homeostatic brake on P2X3. Whole-cell patch clamp in rat DRG neurons; PLC inhibitor (U73122); exogenous PIP2 injection; immunolocalization Molecular Pharmacology Medium 23249537
2013 CASK (calcium/calmodulin-dependent serine protein kinase) interacts with P2X3 receptors in a state-dependent (activation-dependent) manner; this interaction modulates P2X3 receptor stability and efficiency at the neuronal membrane, linking synaptic scaffolding to P2X3 function. Co-immunoprecipitation; state-dependent interaction assays in sensory neurons (as described in review citing primary work) Frontiers in Cellular Neuroscience Low 24363643
2015 Pirt, a transmembrane protein expressed in peripheral neurons, physically interacts with P2X3 via its N-terminal 14 amino acids and inhibits P2X3-mediated currents: Pirt deficiency increased α,β-meATP-evoked currents in bladder DRG neurons; Pirt co-localized with P2X3 in bladder nerve fibers; heterologous Pirt expression reduced P2X3 currents; TAT-Pirt(N14) peptide mimicked inhibition and alleviated bladder overactivity in Pirt−/− and CYP-treated mice. Pirt-KO mouse model; patch clamp electrophysiology; heterologous co-expression; Co-immunoprecipitation; TAT-peptide inhibition in vivo; cystometry Nature Communications High 26151598
2015 NF-κB p65 subunit binds the demethylated P2X3R gene promoter to upregulate P2X3 expression in diabetic neuropathic pain: STZ-diabetic rats showed CpG demethylation of the p2x3r promoter, decreased DNMT3b, enhanced p65 binding to the promoter, and increased P2X3 expression and function; lentiviral p65-siRNA or p65 inhibitors suppressed P2X3 activity and pain hypersensitivity. ChIP assay; bisulfite sequencing; lentiviral siRNA knockdown; western blot; patch clamp electrophysiology; behavioral pain testing Diabetes High 26130762
2016 X-ray crystal structures of human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/desensitized, and antagonist-bound states reveal: (1) an intracellular 'cytoplasmic cap' that stabilizes the open state and creates phospholipid-lined lateral fenestrations for ion egress; (2) competitive antagonists TNP-ATP and A-317491 stabilize the resting/apo state; (3) full gating cycle conformational rearrangements. X-ray crystallography (multiple states); structure-function analysis Nature High 27626375
2018 A negative allosteric site on P2X3 receptors—formed by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains—was identified by X-ray crystallography and mutagenesis: allosteric inhibitors AF-353 and AF-219 bind this site and modulate ATP activation by altering LF, DF, and LB domain conformations, defining the molecular basis of non-competitive P2X3 inhibition. X-ray crystallography; computational modeling; functional mutagenesis of P2X3 channel domains; electrophysiology Proceedings of the National Academy of Sciences High 29674445
2018 ASIC3 and P2X3 receptors form a tight protein complex (confirmed by Co-IP and BN-PAGE/SDS-PAGE analysis) in which ASIC3 stimulation strongly inhibits P2X3 currents partly via a Ca2+-dependent mechanism and the two channels switch ionic permeabilities during activation; the proton-binding site on ASIC3 is critical for this inhibitory crosstalk. Patch clamp; Co-immunoprecipitation; Blue-native PAGE; Ca2+ removal experiments; mutagenesis of proton-binding site; in vivo pain measurements Nature Communications High 29636447
2019 Human P2X3 receptors are activated by Ca2+-ATP and Mg2+-ATP via an acidic chamber near the nucleotide-binding pocket that accommodates divalent cations in distinct modes in the absence and presence of nucleotide; cooperative engagement of divalent ion, receptor, and γ-phosphate of ATP slows ATP unbinding and prolongs recovery from desensitization, a mechanism for limiting channel activity. X-ray crystallography of human P2X3 with divalent-ATP complexes; molecular dynamics simulations; site-directed mutagenesis; functional electrophysiology eLife High 31232692
2019 MK-7264 (gefapixant) is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors that acts preferentially on closed (resting) channels: wash-on experiments with the slowly desensitizing P2X2/3 heteromer showed concentration- and state-dependent inhibition with faster rates and greater inhibition when applied before agonist. Whole-cell patch clamp in 1321N1 cells expressing human P2X3 and P2X2/3; state-dependent wash-on/wash-off kinetic analysis British Journal of Pharmacology Medium 30927255
2019 Aurintricarboxylic acid (ATA) is a nanomolar non-competitive allosteric antagonist of P2X3 receptors binding to the negative allosteric site: radioligand binding showed ATA does not compete with ATP; site-directed mutagenesis and molecular docking mapped ATA binding to the same allosteric site identified by crystallography; ATA also inhibits native P2X3 in mouse DRG neurons. Two-electrode voltage clamp in Xenopus oocytes; patch clamp in mouse DRG; radioligand binding competition; site-directed mutagenesis; molecular docking Neuropharmacology Medium 31461640
2020 Wnt5b/Ryk signaling promotes membrane trafficking of P2X3 receptors via CaMKII activation: Wnt5b elevated membrane P2X3 protein and α,β-meATP-evoked currents in DRG neurons; anti-Ryk antibody or CaMKII inhibitor KN93 blocked Wnt5b-induced membrane P2X3 upregulation and reversed bone cancer pain hypersensitivity. DRG neuron culture; western blot of membrane fractions; patch clamp; CaMKII inhibitor; anti-Ryk antibody; intrathecal injections in cancer pain model Experimental Neurology Medium 32979370
2021 GPR151 couples physically with P2X3 ion channels in DRG neurons and promotes their functional activity: GPR151 conditional KO suppressed P2X3-mediated calcium elevation and neuropathic pain behavior; GPR151 overexpression enhanced P2X3-mediated calcium signaling and DRG excitability; GPR151 KO also blocked CCI-induced CSF1 upregulation and spinal microglial activation, placing GPR151 upstream of P2X3 in a nociceptor-to-CNS signaling cascade. Conditional Gpr151 KO; GPR151 overexpression; Ca2+ imaging; co-immunoprecipitation (implied by coupling); DRG excitability electrophysiology; CSF1/microglial activation assays; human DRG co-expression confirmation Brain High 34244727
2023 P2X3 receptors are upregulated two-fold in peripheral chemosensory afferents (carotid body) in heart failure; P2X3 antagonism abolished episodic burst discharges coinciding with disordered breathing, normalized chemoreceptor sensitivity and breathing, reinstated autonomic balance, improved cardiac function, and reduced inflammation, identifying aberrant ATP/P2X3 signaling in the carotid body as a pathogenic driver of heart failure progression. Heart failure rat model; carotid body electrophysiology (afferent discharge recording); P2X3 antagonist pharmacology; autonomic/cardiac function measurements; western blot for P2X3 expression Nature Communications High 36977675

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 867 7566120
1999 Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. The European journal of neuroscience 706 10103088
1998 The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Molecular and cellular neurosciences 387 9828090
2000 Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 361 11069182
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) 242 35248186
2016 X-ray structures define human P2X(3) receptor gating cycle and antagonist action. Nature 209 27626375
2002 Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 205 12223568
1999 Localization of ATP-gated P2X2 and P2X3 receptor immunoreactive nerves in rat taste buds. Neuroreport 134 10321492
2008 Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Molecular neurobiology 124 18459072
2001 Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU international 122 11412212
2010 AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. British journal of pharmacology 105 20590629
2010 Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain : a journal of neurology 105 20802203
1998 Ultrastructural localization of P2X3 receptors in rat sensory neurons. Neuroreport 99 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 90 17110047
2003 Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert opinion on therapeutic targets 88 12885270
2018 Druggable negative allosteric site of P2X3 receptors. Proceedings of the National Academy of Sciences of the United States of America 83 29674445
2019 BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulmonary pharmacology & therapeutics 79 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 79 30927255
2019 Electroacupuncture Stimulation Alleviates CFA-Induced Inflammatory Pain Via Suppressing P2X3 Expression. International journal of molecular sciences 72 31269659
2015 Promoted Interaction of Nuclear Factor-κB With Demethylated Purinergic P2X3 Receptor Gene Contributes to Neuropathic Pain in Rats With Diabetes. Diabetes 72 26130762
2021 GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation. Brain : a journal of neurology 71 34244727
2011 Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Molecular pain 67 21851615
2004 P2X2 and P2X3 purinoceptors in the rat enteric nervous system. Histochemistry and cell biology 61 14767775
2015 Enhanced binding capability of nuclear factor-κB with demethylated P2X3 receptor gene contributes to cancer pain in rats. Pain 59 26049406
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 57 25809868
2013 ATP P2X3 receptors and neuronal sensitization. Frontiers in cellular neuroscience 57 24363643
2006 The suramin analog 4,4',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (NF110) potently blocks P2X3 receptors: subtype selectivity is determined by location of sulfonic acid groups. Molecular pharmacology 55 16551782
2012 Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. Neuropharmacology 51 23186588
2004 VR1-, VRL-1- and P2X3 receptor-immunoreactive innervation of the rat temporomandibular joint. Brain research 50 15081392
2008 Expression of P2X3 receptor in the trigeminal sensory nuclei of the rat. The Journal of comparative neurology 49 18067147
2010 Sensory purinergic receptor P2X3 is elevated in burning mouth syndrome. International journal of oral and maxillofacial surgery 48 20418063
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
2012 P2X₃ and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons. Neuroscience 47 23201260
2005 Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons. European journal of pharmacology 47 16181623
2005 Developmental regulation of neuron-specific P2X3 receptor expression in the rat cochlea. The Journal of comparative neurology 46 15736235
2003 Intraganglionic laminar endings in the rat esophagus contain purinergic P2X2 and P2X3 receptor immunoreactivity. Anatomy and embryology 46 14624359
2018 Suppressing PKC-dependent membrane P2X3 receptor upregulation in dorsal root ganglia mediated electroacupuncture analgesia in rat painful diabetic neuropathy. Purinergic signalling 45 30084084
2013 17β-estradiol rapidly attenuates P2X3 receptor-mediated peripheral pain signal transduction via ERα and GPR30. Endocrinology 45 23610132
2017 P2X3 receptor involvement in endometriosis pain via ERK signaling pathway. PloS one 44 28898282
2019 Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. eLife 43 31232692
2009 Double P2X2/P2X3 purinergic receptor knockout mice do not taste NaCl or the artificial sweetener SC45647. Chemical senses 43 19833661
2005 Developmentally regulated expression of the P2X3 receptor in the mouse cochlea. Histochemistry and cell biology 43 16341871
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 42 35028015
2022 Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough. The European respiratory journal 41 34649978
2006 Selective labeling of central and peripheral sensory neurons in the developing zebrafish using P2X(3) receptor subunit transgenes. Neuroscience 40 16413125
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
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2007 Neuronal expression of P2X3 purinoceptors in the rat retina. Neuroscience 38 17367943
2012 The effects of electroacupuncture on the extracellular signal-regulated kinase 1/2/P2X3 signal pathway in the spinal cord of rats with chronic constriction injury. Anesthesia and analgesia 37 23223107
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
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2000 Embryonic expression of a P2X(3) receptor encoding gene in zebrafish. Mechanisms of development 35 11091083
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2011 Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Molecular pain 33 21958474
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2008 Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes. Osteoarthritis and cartilage 28 18448363
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2011 Characterization of three diaminopyrimidines as potent and selective antagonists of P2X3 and P2X2/3 receptors with in vivo efficacy in a pain model. British journal of pharmacology 26 21410458
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2003 2', 3'-O-(2,4,6,trinitrophenyl)-ATP and A-317491 are competitive antagonists at a slowly desensitizing chimeric human P2X3 receptor. British journal of pharmacology 25 12967950
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
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2009 The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation. Cellular and molecular neurobiology 24 19960242
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