Affinage

P2RX2

P2X purinoceptor 2 · UniProt Q9UBL9

Length
471 aa
Mass
51.8 kDa
Annotated
2026-04-29
100 papers in source corpus 42 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RX2 encodes an ATP-gated cation channel that assembles as a homotrimer or as obligate heteromers with P2X3 (1:2 stoichiometry), P2X6 (2:1), or P2X5 subunits, each combination conferring distinct pharmacology and desensitization kinetics (PMID:7566120, PMID:22378790, PMID:10864944, PMID:22442090). ATP binds at intersubunit clefts in the extracellular domain—engaging Lys69, Lys308, Arg290, and Glu167—disrupting a closed-state Glu167–Arg290 salt bridge and triggering counter-clockwise rotation and separation of TM2 helices through a gate formed by Asn333–Thr339, with Gly344 conferring voltage dependence (PMID:23041661, PMID:19906973, PMID:19114637, PMID:21576497). Desensitization is tuned by C-terminal splice variation (P2X2a vs. P2X2b), PKC phosphorylation of N-terminal Thr18, PKA phosphorylation of C-terminal Ser431, phosphoinositide binding at Lys365/Lys369, and redox sensing via intracellular Cys430, while conformational rearrangements of the cytosolic domain drive pore dilation independently of pannexin-1 (PMID:9658396, PMID:10744703, PMID:9603227, PMID:16857707, PMID:19793987, PMID:18689682). Dominant-negative P2RX2 mutations (p.V60L) cause progressive sensorineural hearing loss in humans, consistent with the channel's role in cochlear endolymph homeostasis and the severe hearing loss of P2rx2-null mice (PMID:23345450).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Demonstration that P2X2 and P2X3 coassemble into a heteromeric ATP-gated channel in sensory neurons established the heteromerization principle for the P2X family and explained native DRG ATP currents that no single subunit could reproduce.

    Evidence Coexpression of P2X2+P2X3 in Xenopus oocytes recapitulated DRG neuron ATP current properties by voltage-clamp electrophysiology

    PMID:7566120

    Open questions at the time
    • Subunit stoichiometry not determined
    • Physical association not yet shown biochemically
    • No structural information on assembly interface
  2. 1997 High

    Cross-immunoprecipitation provided the first direct biochemical proof that P2X2 and P2X3 physically associate rather than merely coexist, and showed the heteromer has distinct desensitization properties.

    Evidence Epitope-tagged P2X2/P2X3 co-IP from baculovirus-infected insect cells plus electrophysiology

    PMID:9254665

    Open questions at the time
    • Stoichiometry still undetermined
    • Native tissue confirmation lacking
  3. 1998 High

    Multiple regulatory axes of P2X2 were identified simultaneously: extracellular pH enhancement of ATP affinity, PKA phosphorylation of Ser431 reducing current amplitude, glycosylation requirements for surface expression, and C-terminal splice variation controlling desensitization—establishing the channel as an integrator of multiple signaling inputs.

    Evidence pH titration in oocytes (PMID:8730726, 9257926); S431C mutagenesis with PKA dialysis in HEK293 (PMID:9603227); triple N-glycosylation site mutagenesis plus tunicamycin (PMID:9778359); P2X2a/P2X2b splice variant characterization in GT1/HEK293 cells (PMID:9658396)

    PMID:8730726 PMID:9257926 PMID:9603227 PMID:9658396 PMID:9778359

    Open questions at the time
    • Structural basis for pH sensing unknown
    • Whether PKA and splice regulation are independent or synergistic
    • Relative expression of splice variants across tissues incompletely mapped
  4. 2000 High

    PKC phosphorylation of N-terminal Thr18 was identified as a second kinase-dependent desensitization switch, and P2X2/6 heteromeric channels with distinct pharmacology were functionally characterized, broadening the combinatorial diversity of P2X2-containing receptors.

    Evidence T18A/T18N mutagenesis plus phosphothreonine immunodetection in oocytes (PMID:10744703); P2X2/P2X6 coexpression pharmacology in oocytes (PMID:10864944)

    PMID:10744703 PMID:10864944

    Open questions at the time
    • In vivo relevance of PKC regulation not tested
    • P2X2/6 stoichiometry undetermined at this point
  5. 2004 High

    The trimeric quaternary structure of homomeric P2X2 was established biochemically, and real-time FRET measurements revealed that cytosolic domain conformational rearrangements drive pore dilation—linking structure to the progressive permeability change.

    Evidence Chemical cross-linking and co-expression studies (PMID:15313628); AFM and antibody angle measurements (PMID:15657042); CFP/YFP FRET with simultaneous electrophysiology and membrane tethering rescue (PMID:15548662)

    PMID:15313628 PMID:15548662 PMID:15657042

    Open questions at the time
    • Atomic resolution structure not yet available
    • Identity of cytosolic domain conformational change not resolved at residue level
  6. 2004 High

    Alanine-scanning of TM1 and TM2 revealed that both transmembrane domains undergo activation-dependent conformational changes, and identified Y43A/F44A as constitutively active mutants, establishing that the pore is not a passive conduit but an actively gated structure.

    Evidence Systematic Ala-scanning mutagenesis with whole-cell patch-clamp in HEK293 cells

    PMID:15317863

    Open questions at the time
    • Movement of TM1 relative to TM2 during gating not resolved
    • No cryo-EM or crystal structure to interpret mutant phenotypes
  7. 2005 High

    Zinc potentiation was localized to an intersubunit site (His120–His213 from adjacent subunits), and Fe65 was identified as a postsynaptic interacting partner that modulates P2X2 ionic selectivity changes—expanding the regulatory landscape beyond lipids and kinases.

    Evidence Concatamer and disulfide trapping approaches for zinc site (PMID:15899882); yeast two-hybrid, co-IP from brain, and immunogold EM for Fe65 (PMID:16330549)

    PMID:15899882 PMID:16330549

    Open questions at the time
    • Fe65 interaction domain on P2X2 not finely mapped
    • Physiological relevance of Fe65 modulation in synaptic signaling untested
  8. 2006 High

    Phosphoinositide binding at C-terminal Lys365/Lys369 was shown to regulate desensitization and pore dilation, and P2X2/3 heteromer stoichiometry (1P2X2:2P2X3) was defined by mutational rescue, resolving two long-standing questions about channel regulation and assembly.

    Evidence PI3K inhibition plus K365Q/K369Q mutagenesis plus GST pull-down (PMID:16857707); K-to-A mutagenesis rescue in coexpression (PMID:16840712)

    PMID:16840712 PMID:16857707

    Open questions at the time
    • Whether PIP2 binds directly in the lipid bilayer or as a soluble headgroup unclear
    • Stoichiometry defined functionally—structural confirmation needed
  9. 2008 High

    Patch-clamp coordinated spectroscopy with tetracysteine labels demonstrated that P2X2 pore dilation (I2 state) is an intrinsic channel property driven by cytosolic domain rearrangements, ruling out pannexin-1 as the large-pore conduit, and VILIP1 was identified as a calcium-dependent signaling partner regulating P2X2 surface expression and lateral mobility.

    Evidence Biarsenical fluorophore spectroscopy with Panx1 knockout comparison (PMID:18689682); co-IP from brain, surface expression, and lateral diffusion assays (PMID:18922787)

    PMID:18689682 PMID:18922787

    Open questions at the time
    • Structural basis of I2 state at atomic level unknown
    • VILIP1 binding site on P2X2 not mapped
  10. 2009 High

    The TM2 gate region was precisely defined (Asn333–Thr339) with opening involving counter-clockwise helix rotation, Gly344 was identified as the structural basis for voltage-dependent gating, and Cys430 was established as an intracellular redox sensor—together providing a nearly complete gating mechanism.

    Evidence SCAM with MTSET on systematic TM2 mutants plus single-channel recording (PMID:19906973); Gly344 scanning mutagenesis with kinetic modeling (PMID:19114637); chimera/mutagenesis/alkylation convergence on Cys430 (PMID:19793987)

    PMID:19114637 PMID:19793987 PMID:19906973

    Open questions at the time
    • No high-resolution structure of P2X2 in open vs. closed state
    • Coupling between redox sensing and gating machinery not mechanistically detailed
  11. 2012 High

    ATP binding was localized to intersubunit clefts with fewer than three occupied sites sufficient for activation, and the Glu167–Arg290 closed-state salt bridge was shown to be disrupted by ATP binding to allow Arg290 to coordinate the γ-phosphate—completing the ligand-to-gate transduction pathway.

    Evidence Concatamers with defined binding site knockouts (PMID:22828800); charge-reversal mutagenesis, mutant cycle analysis, and state-dependent disulfide trapping (PMID:23041661); covalent ATP-analog tethering at N140/L186 (PMID:21576497); stoichiometry of P2X2/3 and P2X2/6 by binding-site mutagenesis (PMID:22378790)

    PMID:21576497 PMID:22378790 PMID:22828800 PMID:23041661

    Open questions at the time
    • No crystal or cryo-EM structure of P2X2 itself
    • Cooperativity between binding sites not quantitatively resolved
    • Subunit rearrangement pathway from agonist binding to gate opening not structurally visualized
  12. 2013 High

    A human P2RX2 missense mutation (p.V60L) was shown to abolish channel function in a dominant-negative fashion, and P2rx2-null mice developed progressive hearing loss, establishing P2RX2 as a deafness gene and linking its channel activity to cochlear homeostasis.

    Evidence Electrophysiology and FM1-43 uptake of V60L mutant, P2rx2-null mouse audiometry, human genetic co-segregation

    PMID:23345450

    Open questions at the time
    • Precise mechanism by which P2X2 loss impairs cochlear function (endolymph composition vs. hair cell signaling) not resolved
    • Genotype–phenotype correlation across different P2RX2 mutations incomplete
  13. 2020 High

    P2X2 was identified as the ATP receptor on enteric glial cells that drives p38 MAPK-dependent gliosis, cytokine release, and intestinal dysmotility, extending the channel's physiological roles beyond the nervous system and hearing.

    Evidence Genetic depletion and pharmacological antagonism (ambroxol) of P2X2, p38 MAPK pathway analysis in murine and human intestine

    PMID:33332729

    Open questions at the time
    • Downstream targets of p38 MAPK in enteric glia not fully characterized
    • Whether P2X2 homomers or heteromers mediate enteric gliosis not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of P2X2 in multiple conformational states (closed, open, desensitized) has not been determined, leaving the precise atomic-level gating mechanism, the structural basis of pore dilation, and the mechanism of allosteric modulation by CO, pH, and zinc incompletely resolved.
  • No P2X2 crystal or cryo-EM structure in any state
  • Mechanism of CO potentiation at molecular level unknown
  • Structural basis for phosphoinositide-dependent desensitization control not visualized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-382551 Transport of small molecules 3 R-HSA-162582 Signal Transduction 2 R-HSA-9709957 Sensory Perception 2
Partners
APBB1CHRNA6GABRB3P2RX3P2RX5P2RX6VSNL1
Complex memberships
P2X2 homotrimerP2X2/3 heteromer (1:2)P2X2/5 heteromerP2X2/6 heteromer (2:1)

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 P2X2 and P2X3 subunits heteropolymerize to form a novel ATP-gated ion channel in sensory neurons; coexpression of P2X2 and P2X3 (but not other combinations) in Xenopus oocytes reproduced the ATP-gated currents of dorsal root ganglion neurons, indicating heteromeric channel formation. Xenopus oocyte coexpression, voltage-clamp electrophysiology Nature High 7566120
1997 P2X2 and P2X3 subunits physically associate to form heteromeric channels with distinct agonist sensitivity and desensitization properties; cross-immunoprecipitation with epitope-tagged subunits in baculovirus-infected insect cells provided direct biochemical evidence for heteromeric assembly. Baculovirus expression in insect cells, cross-immunoprecipitation, whole-cell electrophysiology The Journal of Neuroscience High 9254665
2005 P2X2 receptors are trimers; chemical cross-linking produced higher-order adducts consistent with trimers, AFM imaging gave mean molecular volume of ~409 nm³ consistent with a trimer, and angle measurements between two bound anti-His antibodies on doubly-labeled receptors averaged 123°, indicating trimeric architecture. Chemical cross-linking, atomic force microscopy (AFM), anti-epitope antibody angle measurement The Journal of Biological Chemistry High 15657042
2004 Homomeric P2X2 receptors are trimers; biochemical cross-linking and co-expression studies confirmed trimeric architecture for slowly desensitizing P2X subtypes including P2X2, P2X4, and P2X5, while P2X6 subunits were retained in ER as non-trimeric aggregates. Chemical cross-linking, co-expression studies, Western blot Journal of Molecular Biology High 15313628
2000 A conserved protein kinase C phosphorylation site (TXK/R motif) in the intracellular N-terminus of P2X2, specifically Thr18, controls desensitization kinetics; mutations at Thr18 (T18A, T18N) or K20T converted slow desensitization (>1 min) to fast desensitization (<1 s), and direct phosphorylation of Thr18 by PKC was demonstrated by immunodetection. Interaction between both cytoplasmic domains is also required for slow desensitization. Site-directed mutagenesis, voltage-clamp in Xenopus oocytes, immunodetection of phosphothreonine The Journal of Biological Chemistry High 10744703
1998 PKA phosphorylation of Ser431 in the intracellular C-terminus of P2X2 reduces ATP-activated current amplitude; intracellular perfusion of 8-bromo-cAMP or PKA catalytic subunit reduced current in wild-type but not S431C mutant receptors expressed in HEK293 cells. Site-directed mutagenesis, whole-cell patch-clamp, intracellular dialysis of PKA/cAMP Journal of Neurochemistry High 9603227
1998 N-linked glycosylation at three extracellular asparagine residues (N182, N239, N298) of P2X2 is essential for cell-surface expression; tunicamycin treatment or triple-site mutagenesis abolished ATP responses and drastically reduced surface expression as shown by biotin labeling and immunofluorescence. Site-directed mutagenesis, tunicamycin treatment, surface biotinylation, immunofluorescence, whole-cell recording Biochemistry High 9778359
1998 Alternative splicing of P2X2 generates isoforms (P2X2a and P2X2b/P2X2-2) that differ in their C-terminal sequences; P2X2b lacks Val370-Gln438 and desensitizes rapidly and completely, whereas P2X2a desensitizes slowly and incompletely. Both isoforms have similar EC50 for ATP. Coexpression of both isoforms can reproduce intermediate desensitization rates seen in native somatotrophs. Heterologous expression in GT1/HEK293 cells, Ca2+ imaging, electrophysiology, RT-PCR in enriched pituitary subpopulations Molecular Endocrinology High 9658396
1999 C-terminal residues near the splice site regulate desensitization rate: truncation at Lys369 accelerated desensitization >100-fold; a single Val370 residue slowed desensitization ~70-fold; the hydrophobicity of Val370 (not its exact structure) determines rate; nearby lysines (especially Lys365) also modulate desensitization. Site-directed mutagenesis, two-electrode voltage-clamp in Xenopus oocytes, peptide injection The Journal of Physiology High 10517803
2006 Phosphoinositides (PIP2, PIP3) regulate P2X2 channel desensitization and pore dilation through direct electrostatic interaction with positively charged residues (Lys365, Lys369) in the proximal cytoplasmic C-terminal domain; PI3K inhibition accelerated desensitization, and K365Q/K369Q mutations mimicked this effect and abolished lipid binding in GST pull-down assays. PI3K inhibition, site-directed mutagenesis, two-electrode voltage-clamp, GST pull-down with PIP-coated membranes, fluorescence assay in COS-7 cells The Journal of Physiology High 16857707
2005 Zinc potentiates P2X2 channel opening via an intersubunit binding site formed by His120 and His213 from adjacent subunits; mixing H120A and H213A single mutants restored zinc potentiation, trimeric concatamers showed zinc potentiation correlating with intersubunit histidine pairs, and H120C/H213C formed ectopic intersubunit disulfide bonds detectable by non-reducing Western blot. Site-directed mutagenesis, trimeric concatamer expression, Xenopus oocyte electrophysiology, non-reducing Western blot, redox manipulation The Journal of Biological Chemistry High 15899882
2004 P2X2 channel pore properties (permeability to large cations, inward rectification, ligand sensitivity) depend on channel expression density; Ile328 at the outer pore mouth is critical for these density-dependent changes, as shown by mutagenesis. Variable expression levels in Xenopus oocytes, mutagenesis, two-electrode voltage-clamp The Journal of Physiology Medium 15107474
2004 TM1 and TM2 of P2X2 participate in conformational changes during activation; alanine-scanning mutagenesis identified residues in TM1 (pattern consistent with helix) and TM2 that altered ATP potency, BzATP efficacy, and deactivation kinetics. Y43A and F44A in TM1 produced spontaneously active channels. Alanine-scanning mutagenesis, whole-cell patch-clamp in HEK293 cells The Journal of Neuroscience High 15317863
2007 Thr339 in TM2 is critical for gating; T339S mutation causes constitutive channel opening and 10-fold increase in ATP sensitivity. Lys308 is involved in gating (not just ATP binding): K308A suppresses spontaneous activity of T339S but K69A does not, indicating Lys308 has a gating role distinct from ATP coordination. Site-directed mutagenesis, single-channel and whole-cell recording in HEK293 cells The Journal of Neuroscience High 18032665
2009 Polar residues in TM2 define the channel gate and permeation pathway; Thr336, Thr339, and Ser340 are exposed in the open channel pore (introduction of positive charge greatly enhanced outward currents); Asn333 and Asp349 lie in external and internal vestibules respectively; gate is formed by residues Asn333-Thr339, with channel opening involving counter-clockwise rotation and separation of TM2 helices. Systematic TM2 mutagenesis, MTSET modification, single-channel recordings, Xenopus oocytes The Journal of Neuroscience High 19906973
2004 FRET measurements revealed time-resolved cytosolic gating motions in P2X2 channels that correlate with permeability changes; wild-type and mutant channels that do not undergo permeability changes also show no cytosolic FRET changes; tethering the cytosolic domain to the plasma membrane prevents both permeability change and cytosolic motions. FRET (CFP/YFP on cytosolic domain), simultaneous whole-cell electrophysiology, tethering experiments The Journal of Neuroscience High 15548662
2008 P2X2 receptor permeability dynamics (I2 state) are an intrinsic channel property requiring cytosolic domain rearrangements; Pannexin-1 channels make no detectable contribution. Patch-clamp coordinated spectroscopy with tetracysteine/biarsenical fluorophores measured site-specific conformational changes in the cytosolic domain correlated with permeability increases. Patch-clamp coordinated spectroscopy, tetracysteine tagging, biarsenical fluorophores, Panx-1 knockout comparison Proceedings of the National Academy of Sciences High 18689682
2011 ATP-binding sites are located in intersubunit extracellular cavities; covalent tethering of ATP-analog NCS-ATP to single cysteine mutants at N140 and L186 (from two adjacent subunits, ~18 Å apart) trapped agonist-bound states with distinct functional consequences: labeling at one position impedes gating efficiency, labeling at the other enhances subsequent ATP function. Covalent tethering with thiol-reactive ATP analog, whole-cell and single-channel recording, P2X2 homology modeling Proceedings of the National Academy of Sciences High 21576497
2012 Trimeric P2X2 receptors can be activated by fewer than three ATP molecules; concatamers with only two intact Lys69 binding sites (KKA, KAK, AKK) formed functional channels, with KKA and KAK producing larger currents than AKK, indicating asymmetric contributions from different subunit interfaces. Trimeric concatamers with defined ATP-binding site mutations, Western blot, whole-cell and outside-out patch recording in HEK293 cells Molecular Pharmacology High 22828800
2012 A salt bridge between Glu167 and Arg290 stabilizes the closed state; ATP binding disrupts this bridge, allowing Arg290 to coordinate the γ-phosphate of ATP. Charge-reversal mutagenesis, mutant cycle analysis, and disulfide trapping demonstrated the Glu167/Arg290 interaction in the closed state and its absence in the open state. Homology modeling, charge-reversal mutagenesis, mutant cycle analysis, disulfide trapping, electrophysiology Molecular Pharmacology High 23041661
2006 Ectodomain lysine residues in P2X2 (Lys69 and Lys308) contribute to ATP binding/gating in heteromeric P2X2/3 receptors; P2X2/3 heteromers contain one P2X2 and two P2X3 subunits, as single lysine mutations in P2X2 were rescued by wild-type P2X3 but not vice versa, and double P2X2 lysine mutant was not rescued. Lysine-to-alanine mutagenesis, co-expression in HEK293 cells, whole-cell voltage-clamp Molecular Pharmacology High 16840712
2012 P2X2/3 heteromers contain one P2X2 and two P2X3 subunits, while P2X2/6 heteromers contain two P2X2 and one P2X6 subunit; demonstrated by selective blockade of function using ATP-binding site mutants in each subunit position, confirmed by protein labeling and PAGE. ATP-binding site mutagenesis (non-functional Ala substitutions), patch-clamp, Ca2+ imaging, surface protein labeling and PAGE in HEK293 cells and Xenopus oocytes The Journal of Biological Chemistry High 22378790
2000 Coexpression of P2X2 and P2X6 subunits forms a heteromeric P2X2/6 receptor with distinct pharmacology from homomeric P2X2, including reduced agonist potencies, biphasic ATP currents (especially with Zn2+), narrower pH enhancement range, and altered pH-dependent suramin blockade. Coexpression in Xenopus oocytes, voltage-clamp electrophysiology, pharmacological characterization The Journal of Neuroscience High 10864944
2004 Co-activation of P2X2 and GABAA receptors (containing α and β but not γ subunits) produces cross-inhibition; the C-terminal domain of P2X2 and the intracellular loop of β GABAA subunits are required for this interaction. In hippocampal neurons, P2X2 co-expression with rho1 containing the β3 C-terminal sequence caused co-clustering/retargeting. Co-expression in Xenopus oocytes, minigene overexpression, electrophysiology, hippocampal neuron transfection, immunocytochemistry The Journal of Biological Chemistry High 15456793
2008 The neuronal calcium sensor VILIP1 forms a signaling complex with P2X2 receptors in vitro and in vivo, regulating P2X2 receptor ATP sensitivity, peak response, surface expression, and lateral diffusion; VILIP1-P2X2 interaction is enhanced in an activation- and Ca2+-dependent manner, and is increased during action potential firing conditions in hippocampal neurons. Proteomics/co-IP, in vivo co-immunoprecipitation from brain, electrophysiology, surface expression assay, lateral diffusion measurements Science Signaling High 18922787
2011 Neuronal P2X2 receptor lateral mobility in dendrites is heterogeneous, mostly Brownian, and is increased in an activation-dependent manner; mobility is regulated by cytosolic VILIP1 calcium binding protein. Single-molecule imaging with simultaneous whole-cell voltage-clamp confirmed activation-dependent increased receptor mobility. Single-molecule imaging with quantum dot labels, simultaneous whole-cell voltage-clamp, hippocampal neurons The Journal of Neuroscience High 22090499
2005 Fe65 (a β-amyloid precursor protein binding protein) interacts with the P2X2 C-terminal domain, colocalizes with P2X2 at postsynaptic specializations of excitatory synapses in CA1 hippocampus, and can be co-immunoprecipitated from brain membrane extracts; Fe65 coexpression inhibits the time-dependent change in P2X2 ionic selectivity. Yeast two-hybrid, GST pull-down, co-immunoprecipitation from brain, postembedding immunogold EM, double immunogold labeling, electrophysiology The Journal of Biological Chemistry High 16330549
2011 Disrupting microtubule network with colchicine inhibits dye (Yo-Pro-1) uptake induced by ATP at P2X2 receptors without affecting ionic currents, indicating the cytoskeleton regulates large-pore formation (macropore) but not basic ion channel function of P2X2. Colchicine treatment, Yo-Pro-1 dye uptake assay, electrophysiology in Xenopus oocytes and HEK293 cells British Journal of Pharmacology Medium 21306580
1998 P2X2 receptor function is modulated by extracellular pH; lowering pHe to 6.5 increases ATP affinity ~5-fold without changing maximum activity or agonist potency order; receptor protonation (not agonist protonation) is responsible for the enhancement; suramin blockade is specifically affected by acidification. Voltage-clamp in Xenopus oocytes expressing recombinant P2X2, systematic pH titration, agonist/antagonist pharmacology British Journal of Pharmacology High 8730726 9257926
2009 P2X2 channel gating involves both voltage and ATP binding; the flexibility of Gly344 in TM2 contributes to voltage-dependent gating; a three-state model (fast ATP-binding followed by slower gating step) quantitatively reproduces experimental conductance-voltage relationships. Xenopus oocyte two-electrode voltage-clamp, inside-out patch in HEK293, G344 glycine-scanning mutagenesis, kinetic modeling The Journal of General Physiology High 19114637
2009 Reactive oxygen species (H2O2) and mercury potentiate P2X2a receptor activity through intracellular Cys430; C430A and C430S mutants abolished potentiation; MTSEA alkylation of Cys430 also prevented potentiation; P2X2b (lacking Cys430-containing region) was unaffected, identifying Cys430 as an intracellular redox sensor. Chimeric receptor construction, site-directed mutagenesis, MTSET alkylation, Xenopus oocyte and HEK293 electrophysiology The Journal of Neuroscience High 19793987
2002 P2X2 desensitization depends on coupling between ectodomain and C-terminal domain; chimeric receptors bearing P2X3 ectodomain desensitized in a receptor-subtype-specific and ligand-nonspecific manner, while P2X7 ectodomain chimeras desensitized in a receptor-nonspecific manner; high-efficacy agonists drive stronger desensitization. Chimeric receptor construction, Ca2+ imaging and electrophysiology in HEK293 cells Molecular Pharmacology Medium 12391283
2013 P2RX2 p.V60L mutation abolishes ATP-evoked inward current and ATP-stimulated macropore permeability (FM1-43 dye uptake) in heterologous expression; co-expression of mutant and WT subunits reduces ATP-activated membrane permeability in a dominant-negative fashion; P2RX2-null mice develop severe progressive hearing loss and increased noise susceptibility. Heterologous expression electrophysiology, FM1-43 dye uptake, P2RX2-null mouse audiometry, human genetic co-segregation Proceedings of the National Academy of Sciences High 23345450
2012 P2X2 and P2X5 subunits associate to form heteromeric receptors with alternate stoichiometries present at the plasma membrane; P2X2/5 receptors display pore dilatation, membrane blebbing, and phosphatidylserine exposure characteristic of P2X7 receptors. Demonstrated by BRET, BiFC, and protein biochemistry in rat brain neurons where P2X2 and P2X5 colocalize. BRET, bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, confocal colocalization in neurons The Journal of Neuroscience Medium 22442090
2011 In mouse spermatozoa, the ATP-activated cation current in the midpiece is mediated by P2X2 receptor; the current is absent in P2rx2−/− mice and has biophysical/pharmacological properties matching heterologously expressed P2X2. P2rx2−/− males show declining fertility with frequent mating. Whole-spermatozoa patch-clamp, P2rx2 knockout mice, pharmacological profiling Proceedings of the National Academy of Sciences High 21831833
2020 P2X2 is the relevant ATP receptor on enteric glial cells (EGCs) mediating enteric gliosis; ATP activation of P2X2 triggers a p38 MAPK-dependent pathway causing cytokine release and gliosis phenotype; P2X2 receptor antagonism (including novel antagonist ambroxol) prevented ATP-induced enteric gliosis, inflammation, and dysmotility in murine and human intestine. P2X2 genetic depletion, receptor antagonism, p38 MAPK pathway analysis, in vivo mouse models, human intestine experiments EMBO Molecular Medicine High 33332729
1998 P2X2 receptor activity is modulated by extracellular ATP-activated MAP kinases in PC12 cells; calcium influx through P2X2 receptors (not voltage-gated Ca2+ channels) activates ERK1/2 via Pyk2 tyrosine phosphorylation; response requires extracellular calcium and is blocked by suramin. Western blot for ERK/Pyk2 phosphorylation, pharmacological dissection (suramin, voltage-gated Ca2+ channel blockers), PC12 cells The Journal of Biological Chemistry Medium 9685331
2011 GABAA receptors and P2X2 receptors form a transient complex intracellularly that facilitates co-trafficking to the cell surface where they are located primarily extrasynaptically; P2X2 activation causes Ca2+-dependent and Ca2+-independent increases in GABAA receptor mobility and degradation, while P2X2 receptors are stabilized and form larger clusters. Co-immunoprecipitation in HEK293 cells, FRET, single particle tracking in spinal cord neurons The Journal of Biological Chemistry Medium 21343285
2015 α6-containing nicotinic acetylcholine receptors (α6* nAChRs) directly interact with and cross-inhibit P2X2/3 receptors in DRG nociceptors; this interaction contributes to nicotine analgesia; demonstrated by physical interaction between receptors and requirement of α6* (but not α4*) nAChRs for peripheral/spinal nicotine analgesia. Gain- and loss-of-function nAChR mutants, expression genomics, DRG electrophysiology, behavioral pain models Science Translational Medicine Medium 25972004
2009 Carbon monoxide (CO) is a potent and selective positive modulator of P2X2 (homomeric) receptors; CO and CO-donor CORM-2 enhanced ATP-evoked P2X2 currents but caused small inhibition of P2X2/3 and P2X4 and had no effect on P2X3; the effect is independent of soluble guanylyl cyclase/cGMP pathway. Whole-cell patch-clamp in HEK293 expressing recombinant receptors and in native PC12 cells, CO donor pharmacology, guanylyl cyclase inhibition British Journal of Pharmacology Medium 19694727
2001 Cochlear outer sulcus cells (OSC) and vestibular transitional cells (VTC) mediate P2X2-dependent parasensory cation absorption; ATP-stimulated transepithelial current in both cell types showed P2X2 pharmacological profile (ATP>BzATP>αβmeATP potency order, blocked by suramin and gadolinium), mediating endolymph ionic homeostasis. Vibrating probe current measurement, pharmacological profiling with P2X2-selective agonist/antagonist profile The Journal of Neuroscience Medium 11717350

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 Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system. The Journal of comparative neurology 226 10213185
2005 Atomic force microscopy imaging demonstrates that P2X2 receptors are trimers but that P2X6 receptor subunits do not oligomerize. The Journal of biological chemistry 156 15657042
2000 Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 155 10899177
1999 Expression of the P2X(2) receptor subunit of the ATP-gated ion channel in the cochlea: implications for sound transduction and auditory neurotransmission. The Journal of neuroscience : the official journal of the Society for Neuroscience 149 10493739
2000 A protein kinase C site highly conserved in P2X subunits controls the desensitization kinetics of P2X(2) ATP-gated channels. The Journal of biological chemistry 148 10744703
2008 P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. American journal of physiology. Lung cellular and molecular physiology 135 18689601
1999 Localization of ATP-gated P2X2 and P2X3 receptor immunoreactive nerves in rat taste buds. Neuroreport 134 10321492
1997 Effects of extracellular pH on agonism and antagonism at a recombinant P2X2 receptor. British journal of pharmacology 132 9257926
1996 Full sensitivity of P2X2 purinoceptor to ATP revealed by changing extracellular pH. British journal of pharmacology 122 8730726
2013 Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences of the United States of America 119 23345450
2011 Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: implications for its therapeutic action. British journal of pharmacology 111 21306580
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