Affinage

P2RX4

P2X purinoceptor 4 · UniProt Q99571

Length
388 aa
Mass
43.4 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2X4 (P2RX4) is an ATP-gated, non-selective cation channel that functions as a Ca2+ entry pathway controlling diverse processes including immune cell migration, inflammation, neuronal sensitization, and cell survival (PMID:17299767, PMID:29894310, PMID:29343707). The functional channel is a trimer assembled from a 388-residue subunit, and only the full-length, N-linked glycosylated form reaches the plasma membrane while the non-glycosylated species remains intracellular and detergent-insoluble (PMID:9511769, PMID:11864978). P2X4 is predominantly stored in lysosomal/endolysosomal compartments, directed there by N-terminal di-leucine-like and C-terminal tyrosine-based trafficking motifs, and its surface availability is gated by regulated lysosomal exocytosis triggered by stimuli such as phagocytosis, chloroquine, CCL2/CCR2 signaling, or extracellular-vesicle cargo (PMID:24935743, PMID:19283779, PMID:22222817, PMID:34404763). Once at the surface, ATP-gated Ca2+ influx through P2X4 drives downstream programs: PI3K/Akt-dependent microglial chemotaxis (PMID:17299767), BDNF-dependent spinal sensitization in sensory neurons during inflammatory and neuropathic pain (PMID:29343707, PMID:37860691), NLRP3 inflammasome activation (PMID:32086866), and a mitochondria-coupled feed-forward Ca2+/ATP loop sustaining T-cell polarization and migration (PMID:29894310, PMID:35119925). At endolysosomal membranes the channel forms a Ca2+-dependent complex with calmodulin to promote membrane fusion and vacuolation (PMID:26101220). P2X4 assembles into heteromeric channels with P2X6 and P2X1 subunits, each conferring distinct pharmacology (PMID:9736638, PMID:15686495), and physically associates with P2X7 in an ATP-driven manner that potentiates P2X7-mediated pore formation, IL-1β release, and cell death through P2X4-supplied Ca2+ influx (PMID:17785580, PMID:26456657, PMID:22349510). Prolonged activation drives a non-cytolytic, phosphoinositide-regulated, pannexin-independent pore dilation permeable to large organic cations (PMID:22318986). The channel is allosterically potentiated by ivermectin, which slows desensitization and enables pore dilation (PMID:24917516), and inhibited by selective allosteric antagonists such as BX430; cryo-EM defines a shared allosteric antagonist site at extracellular subunit interfaces that locks the channel against activation (PMID:25597706, PMID:37833294). In disease contexts P2X4 senses osteoblast PANX3-released ATP to maintain bone-marrow plasma cell survival via ER homeostasis (PMID:38355795) and transduces dying-cell ATP into mTOR-dependent pro-survival, ROS-driven programs in colorectal cancer (PMID:36385525).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 Medium

    Establishing the molecular identity of human P2X4 and which transcript is functional defined the channel-forming unit and showed that an alternatively spliced variant cannot form a channel.

    Evidence Xenopus oocyte cRNA expression with electrophysiology and transcript mapping of full-length vs. spliced human P2X4

    PMID:9511769

    Open questions at the time
    • Did not define subunit stoichiometry
    • No structural information on the channel
  2. 1998 High

    Demonstrating co-assembly of P2X4 with P2X6 established that P2X4 forms heteromeric channels with novel pharmacology rather than acting only as a homomer.

    Evidence Co-purification of epitope-tagged subunits from HEK-293 cells plus two-electrode voltage-clamp in oocytes

    PMID:9736638

    Open questions at the time
    • Native tissue contribution of P2X4/P2X6 heteromers not established
    • Stoichiometry within the heteromer not resolved
  3. 2002 High

    Identifying N-linked glycosylation as a requirement for surface expression explained how the channel is gated at the level of trafficking and showed a cardiac inotropic function.

    Evidence Tunicamycin glycosylation block, surface biotinylation, antisense knockdown and Ca2+/contractility assays in cardiac myocytes

    PMID:11864978

    Open questions at the time
    • Specific glycosylation sites not mapped here
    • Did not address lysosomal retention motifs
  4. 2005 High

    Showing P2X1+P2X4 form trimeric heteromers extended the subunit-combination repertoire and revealed mixed kinetic/pharmacological phenotypes.

    Evidence His-tag affinity co-purification with BN-PAGE size confirmation and oocyte electrophysiology

    PMID:15686495

    Open questions at the time
    • In vivo relevance of P2X1/P2X4 heteromers unknown
    • Tissue distribution of the heteromer not defined
  5. 2007 High

    Linking P2X4 Ca2+ influx to PI3K/Akt downstream of P2Y12 defined a mechanistic role in ATP-induced microglial chemotaxis.

    Evidence Dunn chamber chemotaxis, PI3K inhibitors, Akt phosphorylation readout, and lentiviral shRNA knockdown

    PMID:17299767

    Open questions at the time
    • Did not establish how P2X4 reaches the surface during chemotaxis
    • Connection to lysosomal trafficking not yet made
  6. 2007 High

    Demonstrating physical P2X4–P2X7 association that increases P2X4 surface fraction and shapes P2X7 currents framed P2X4 as a modulator of P2X7 signaling.

    Evidence Reciprocal Co-IP from HEK293 cells and macrophages, surface biotinylation, dominant-negative mutagenesis and patch clamp

    PMID:17785580

    Open questions at the time
    • Whether a stable heteromeric channel forms vs. functional crosstalk was not fully resolved
    • Stoichiometry of the association unknown
  7. 2009 High

    Showing lysosomal storage of P2X4 and stimulus-triggered surface delivery revealed that functional channel availability is controlled post-translationally by exocytosis, not total expression.

    Evidence Surface biotinylation, patch clamp and pharmacological lysosomal secretion (phagocytosis, chloroquine) in alveolar macrophages

    PMID:19283779

    Open questions at the time
    • Trafficking motifs responsible not yet identified
    • Molecular machinery of the exocytic step undefined
  8. 2012 High

    A cluster of studies defined how surface P2X4 is dynamically regulated: CCL2/CCR2-driven lysosomal exocytosis delivers it to the membrane, ATP-induced Ca2+ and p38 MAPK control its lateral mobility, and prolonged activation drives phosphoinositide-dependent, pannexin-independent pore dilation.

    Evidence Surface biotinylation, GFP-P2X4 live imaging and β-hexosaminidase release; quantum-dot single-molecule tracking; dye-uptake/patch clamp with carbenoxolone and wortmannin in microglia

    PMID:22222817 PMID:22318986 PMID:22393055

    Open questions at the time
    • Molecular identity of the dilated permeation pathway not structurally defined
    • p38 MAPK target on P2X4 not identified
  9. 2012 Medium

    Dissecting P2X4 contribution to P2X7 outcomes showed P2X4-supplied Ca2+ influx is required for P2X7-dependent macrophage death but not for pore formation or MAPK signaling.

    Evidence shRNA knockdown with Ca2+ imaging, pore assays, MAPK westerns and viability in RAW264.7 macrophages

    PMID:22349510

    Open questions at the time
    • Single cell line, single lab
    • Did not resolve whether effect requires physical P2X4–P2X7 complex
  10. 2014 High

    Identifying N-terminal di-leucine and C-terminal tyrosine trafficking motifs and validating a pHluorin reporter explained the molecular basis of lysosomal targeting and clarified that ivermectin acts allosterically rather than by surface delivery.

    Evidence P2X4-pHluorin live imaging across multiple cell types with ivermectin treatment; complementary patch-clamp/mutagenesis kinetic modeling of ivermectin action

    PMID:24917516 PMID:24935743

    Open questions at the time
    • Adaptor proteins reading the motifs not identified
    • Coupling between pore dilation and re-sensitization mechanistically incomplete
  11. 2014 Medium

    Demonstrating activity-dependent, specific inhibition of TRPM6 by P2X4 placed the channel in cation-channel crosstalk regulating Mg2+ handling.

    Evidence Whole-cell patch clamp with ATP-sensitivity mutant and TRPM7/P2X6 specificity controls

    PMID:24413910

    Open questions at the time
    • Molecular mechanism of TRPM6 inhibition undefined (kinase-independent)
    • Single lab, heterologous system
  12. 2015 High

    A set of studies established P2X4 as a Ca2+ source coupling to organelle and cytoskeletal functions: endolysosomal P2X4–calmodulin complexes drive membrane fusion/vacuolation, and indirect ATP-autocrine activation underlies podocyte mechanotransduction.

    Evidence Cell-free endolysosome fusion assay, P2X4–CaM Co-IP and gene disruption; podocyte patch clamp with TRPC knockouts, 5-BDBD and ATP-release measurement

    PMID:26101220 PMID:26160898

    Open questions at the time
    • How channel-localized Ca2+ is spatially restricted to fusion sites not resolved
    • Source of ATP for autocrine activation in podocytes not fully defined
  13. 2015 Medium

    Mapping the ATP-driven P2X7 C-terminal interaction with P2X4 to functional outcomes and developing the selective allosteric antagonist BX430 advanced both mechanism and pharmacology.

    Evidence Co-IP/FRET with P2X4 KO functional readouts (death, dye uptake, IL-1β); calcium/dye-uptake and electrophysiology selectivity profiling for BX430

    PMID:25597706 PMID:26456657

    Open questions at the time
    • BX430 binding site not yet structurally defined at this stage
    • Stoichiometry and physiological prevalence of P2X4–P2X7 complexes unresolved
  14. 2016 Medium

    Identifying presynaptic P2X4 on AgRP-NPY terminals and endothelial P2X4 in ischemic preconditioning broadened the channel's roles into circuit neuromodulation and vascular neuroprotection.

    Evidence BAC reporter mice with slice electrophysiology and leptin/food-deprivation manipulation; P2X4 KO MCAO model with fluid shear stress and osteopontin rescue

    PMID:27173846 PMID:27559172

    Open questions at the time
    • Mechanism coupling shear stress to osteopontin via P2X4 not detailed
    • Presynaptic trafficking control of P2X4 in neurons not defined
  15. 2017 Medium

    FRET evidence that P2X4 and P2X7 are in proximity but coexpression behaves as independent homomers tempered the heteromeric-channel model, favoring functional crosstalk over a dominant heteromer phenotype.

    Evidence FRET with labeled subunits and two-electrode voltage clamp pharmacology in Xenopus oocytes

    PMID:29213241

    Open questions at the time
    • Heterologous system may not reflect native conditions
    • Does not reconcile with functional Ca2+/death crosstalk reported elsewhere
  16. 2018 High

    Three studies linked P2X4 Ca2+ signaling to physiological output: a mitochondria-coupled feed-forward loop sustaining T-cell migration, P2X4-upstream BDNF release driving spinal pain sensitization, and lysosomal-exocytosis-dependent fibrogenesis in hepatic myofibroblasts.

    Evidence Mitochondria/P2X4 colocalization imaging with in vivo lung transplant; P2RX4 KO mice with DRG Ca2+ imaging and spinal phospho-pathway westerns; P2X4 KO fibrosis models with calcium/exocytosis readouts

    PMID:29343707 PMID:29802948 PMID:29894310

    Open questions at the time
    • How localized mitochondrial ATP feeds P2X4 spatially incomplete
    • Direct demonstration of P2X4-triggered BDNF exocytosis vesicle machinery lacking
  17. 2020 High

    Genetic models defined P2X4 roles in inflammasome activation, synaptic plasticity/behavior, and bone-marrow plasma cell survival, the last revealing a PANX3→ATP→P2RX4→ER homeostasis axis.

    Evidence P2X4 KO renal ischemia-reperfusion with inflammasome westerns; internalization-defective P2X4mCherryIN knock-in with LTP/LTD and behavior; Panx3/P2rx4 KO and B-lineage Chop-rescue plasma cell study

    PMID:31911635 PMID:32086866 PMID:38355795

    Open questions at the time
    • How P2X4 Ca2+ couples to NLRP3 assembly not detailed
    • Mechanism linking P2X4 to ATF4/CHOP-controlled ER homeostasis incomplete
  18. 2022 High

    Tumor-context studies established that dying-cell ATP activates P2X4 to drive mTOR/ROS pro-survival signaling in colorectal cancer and that endolysosomal P2X4 supports breast cancer autophagy and EMT.

    Evidence Patient-derived organoids with ATP release, P2X4 inhibition, S6 phosphorylation and ROS scavenging; breast cancer siRNA/rescue with lysosome acidity, autophagy, EMT markers and xenograft

    PMID:35411034 PMID:36385525

    Open questions at the time
    • Link between P2X4 Ca2+ and mTOR activation mechanistically indirect
    • Breast cancer study single lab/Medium confidence
  19. 2023 High

    Cryo-EM of P2X4 with BX430 and BAY-1797 defined a shared allosteric antagonist site at extracellular subunit interfaces, and genetic models established myeloid P2X4 upregulation as necessary for neuropathic tactile allodynia.

    Evidence Cryo-EM structures with structure-based mutagenesis/electrophysiology; global, myeloid-specific KO and P2X4mCherryIN knock-in nerve-injury models with in vivo electrophysiology and TrkB blockade

    PMID:37833294 PMID:37860691

    Open questions at the time
    • Structures are zebrafish P2X4; full human apo/activated states not detailed here
    • Signal coupling microglial P2X4 to TrkB/BDNF in vivo not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single lysosomally-stored channel selectively delivers Ca2+ to such divergent downstream effectors (NLRP3, mTOR, CaM-fusion, BDNF release, ER stress) in a context-specific manner, and which trafficking adaptors and spatial microdomains direct stimulus-specific surface deployment.
  • No unifying model of how P2X4 Ca2+ is decoded into distinct effector pathways
  • Adaptor proteins recognizing the di-leucine/tyrosine motifs unidentified
  • Native human channel structures in distinct functional states lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005764 lysosome 4 GO:0005886 plasma membrane 4 GO:0005768 endosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CALM1P2RX1P2RX6P2RX7PANX3
Complex memberships
P2X1/P2X4 heteromeric channelP2X4/P2X6 heteromeric channelP2X4–P2X7 receptor assemblyP2X4–calmodulin endolysosomal complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 P2X4 and P2X6 subunits co-assemble into heteromeric ATP-gated channels with a novel pharmacological phenotype (sensitive to alpha,beta-methylene ATP, blocked by suramin and Reactive Blue 2), distinct from homomeric P2X4; assembly shown by co-purification from HEK-293 cells with epitope-tagged constructs and functional characterization in Xenopus oocytes. Co-purification/pulldown from HEK-293 cells with epitope-tagged subunits; two-electrode voltage-clamp in Xenopus oocytes The Journal of neuroscience High 9736638
2002 P2X4 receptor is N-linked glycosylated; only the glycosylated 58-kDa form is expressed on the cell surface (non-glycosylated 44-kDa form is detergent-insoluble and intracellular), establishing that N-linked glycosylation is required for plasma membrane localization and detergent solubility. P2X4 mediates the positive inotropic effect of ATP in cardiac myocytes. Tunicamycin treatment to block glycosylation; cell-surface biotinylation with streptavidin pulldown; antisense oligonucleotide knockdown; 45Ca influx assay; contractile amplitude measurement The Journal of biological chemistry High 11864978
2005 P2X1 and P2X4 subunits form heteromeric trimeric receptors; co-purification with hexahistidyl-tagged P2X1 and BN-PAGE confirmed trimeric complexes containing both subunits. Heteromeric P2X1+4 receptors have kinetics resembling homomeric P2X4 but pharmacology (alpha,beta-methylene ATP sensitivity, suramin/TNP-ATP antagonism) resembling homomeric P2X1. Affinity co-purification with His-tagged P2X1; BN-PAGE; two-electrode voltage-clamp in Xenopus oocytes Journal of neurochemistry High 15686495
2007 P2X4 receptor is required for ATP-induced microglial chemotaxis; pharmacological blockade and lentiviral shRNA knockdown of P2X4R both significantly suppressed microglial chemotaxis. P2X4R affects the PI3K/Akt pathway downstream of P2Y12R by contributing calcium influx, since chelating extracellular calcium reduced Akt phosphorylation. Dunn chemotaxis chamber; PI3K inhibitors (wortmannin, LY294002); Akt phosphorylation assay; lentiviral shRNA knockdown; various P2X4R antagonists Glia High 17299767
2007 P2X4 and P2X7 physically associate to form heteromeric receptors: co-immunoprecipitated from HEK293 cells and from bone marrow-derived macrophages. P2X7 increases cell-surface fraction of P2X4 two-fold. A dominant-negative P2X4 mutant (C353W) inhibits P2X7-mediated currents >2-fold, and P2X4S341W co-expressed with P2X7 confers ivermectin potentiation and TNP-ATP sensitivity absent from P2X7 alone. Co-immunoprecipitation from HEK293 cells and macrophages; cell-surface biotinylation; dominant-negative mutagenesis; whole-cell patch clamp Molecular pharmacology High 17785580
2009 P2X4 receptors are predominantly in intracellular lysosomal compartments in alveolar macrophages; phagocytosis of zymosan or chloroquine-induced lysosomal secretion rapidly (within 4 h) increases functional surface P2X4R expression 2–7-fold without changing total protein, while classical activation (IFN-γ/TNF-α or IFN-γ/LPS) reduces surface and functional P2X4R 3-fold without altering total protein. Western blot; cell-surface biotinylation assay; whole-cell patch clamp; chloroquine treatment; phagocytosis stimulation European journal of immunology High 19283779
2012 CCL2/CCR2 signaling promotes trafficking of P2X4R from lysosomal compartments to the cell surface of microglia via lysosomal exocytosis, increasing surface P2X4R without changing total cellular expression; this enhances ATP-induced Akt phosphorylation (a P2X4R-mediated response). Quantitative cell-surface biotinylation assay; time-lapse imaging of GFP-tagged P2X4R; lysosomal enzyme (β-hexosaminidase) release assay; Akt phosphorylation assay; CCR2 antagonist Purinergic signalling High 22222817
2012 Prolonged ATP activation of native P2X4 channels in microglia induces non-cytolytic pore dilation permeable to NMDG+ and large fluorescent dyes; this is independent of pannexin hemichannels (insensitive to carbenoxolone) and is inhibited by wortmannin (PI kinase inhibitor), indicating regulation by phosphoinositide levels. Electrophysiology (patch clamp); dye uptake assay; carbenoxolone blockade; wortmannin treatment in BV-2 and primary murine microglia Glia High 22318986
2012 P2X4 receptor lateral mobility in microglial processes is regulated by ATP-induced calcium influx and the p38 MAPK pathway; ATP activation increases receptor mobility, and p38 MAPK selectively regulates the slowly mobile receptor population in activated microglia. Single-molecule imaging with quantum dot-labeled P2X4 receptors; calcium chelation; p38 MAPK inhibitors; resting vs. LPS-activated microglia The Journal of biological chemistry Medium 22393055
2014 P2X4 receptor is predominantly localized to lysosomes and is targeted there by tyrosine-based and di-leucine-like trafficking motifs in its C-terminal and N-terminal regions, respectively; pHluorin imaging showed cell surface and intracellular fractions are cell-type and compartment-specific, and ivermectin does not increase the PM fraction of P2X4 but acts allosterically. pH-sensitive fluorescent P2X4-pHluorin constructs; live-cell imaging in HEK-293, hippocampal neurons, C8-B4 microglia, ATII cells; ivermectin treatment The Journal of general physiology High 24935743
2014 P2X4 receptor activity-dependently inhibits TRPM6 Mg2+ channel activity; a P2X4 mutant with altered ATP sensitivity failed to inhibit TRPM6, and P2X4 did not inhibit the close homologue TRPM7, demonstrating specificity. Standard kinase inhibitors (PKC, PKA, PI3K) did not prevent this inhibition. Whole-cell patch clamp; P2X4 ATP-sensitivity mutant; P2X6 (non-functional) control; kinase inhibitor panel Pflugers Archiv Medium 24413910
2015 Endolysosomal P2X4 Ca2+ release is required for endolysosomal membrane fusion; P2X4 and calmodulin (CaM) form a complex at endolysosomal membranes, and P2X4 activation recruits CaM to promote fusion and vacuolation in a Ca2+-dependent manner. CaM inhibition suppressed P2X4-triggered fusion and vacuolation. P2X4 overexpression and dominant-negative mutant; cell-free endolysosome fusion assay; vacuole enlargement assay; co-immunoprecipitation of P2X4–CaM complex; CaM inhibitors; P2X4 gene disruption The Journal of cell biology High 26101220
2015 P2X4 channels act as mechanotransducers in podocytes via an indirect mechanism: mechanical stimulation triggers ATP release from podocytes, which then activates P2X4 channels (TRPC6-independent), leading to increased intracellular Ca2+ and actin cytoskeleton reorganization. Mechanically induced currents were significantly decreased by P2X4 blocker 5-BDBD and were insensitive to TRPC1/3/6 knockout or broad TRPC blocker. Patch clamp of podocytes; genetic inactivation of TRPC6, TRPC1/3/6; 5-BDBD pharmacological blockade; fluorometric ATP release assay; actin cytoskeleton imaging Journal of the American Society of Nephrology High 26160898
2015 BX430 is a selective, non-competitive allosteric antagonist of human P2X4 with submicromolar potency (IC50 = 0.54 µM); concentration-response curves show insurmountable blockade consistent with a non-competitive allosteric mechanism. BX430 suppresses both ATP-evoked currents and ivermectin-potentiated membrane permeabilization/pore dilation. Calcium uptake assay; patch-clamp electrophysiology; fluorescent dye uptake (pore dilation); single-cell calcium imaging in THP-1–derived macrophages Molecular pharmacology High 25597706
2015 P2X7 C-terminus interacts with P2X4, and this interaction is driven by ATP; disruption of P2X4 by knockout attenuated P2X7-induced cell death, dye uptake, and IL-1β release in macrophages. Co-immunoprecipitation; FRET experiments; P2X4 knockout macrophages; functional assays (cell death, dye uptake, IL-1β ELISA) Biochemical and biophysical research communications Medium 26456657
2016 In the hypothalamic arcuate nucleus, P2X4 receptors are expressed presynaptically on AgRP-NPY neuron terminals (not on somata) and mediate ATP-facilitated GABA release onto POMC and paraventricular nucleus neurons; presynaptic P2X4 expression and responses are decreased by food deprivation and partially restored by leptin. BAC transgenic tdTomato reporter mice; immunohistochemistry with cell-specific GFP reporter lines; whole-cell electrophysiology in brain slices; food deprivation and leptin treatment The Journal of neuroscience High 27559172
2017 FRET analysis confirms that P2X4 and P2X7 subunits can physically interact (significant FRET signals detected between fluorophore-labeled subunits in Xenopus oocytes); however, functional electrophysiological analysis of coexpressed human P2X4 and P2X7 is consistent with independent homomers only—no novel electrophysiological phenotype attributable to heteromers was detected. FRET with EGFP/TagRFP-labeled subunits in Xenopus oocytes; two-electrode voltage clamp; selective pharmacological inhibitors Frontiers in pharmacology Medium 29213241
2018 SDF-1α triggers mitochondrial ATP production, pannexin-1-dependent ATP release, and localized co-accumulation of mitochondria with P2X4 receptors at the leading edge of T cells; autocrine P2X4 stimulation drives Ca2+ influx and sustains mitochondrial ATP synthesis required for pseudopod protrusion, T cell polarization, and migration. P2X4R antagonism blocked T cell activation and migration in vitro and prevented allograft rejection in a mouse lung transplant model. Live-cell imaging of mitochondria and P2X4 co-localization; Ca2+ imaging; P2X4 inhibition; pannexin-1 blockade; in vitro migration assays; mouse lung transplant model with P2X4 antagonist treatment The Journal of clinical investigation High 29894310
2018 P2RX4 expressed in sensory neurons co-localizes with BDNF and controls Ca2+ influx in DRG neurons; in P2RX4-deficient mice, BDNF-dependent signaling in the dorsal horn (Erk1/2 phosphorylation, GluN1 phosphorylation, KCC2 downregulation) triggered by peripheral inflammation is impaired, placing P2RX4 upstream of neuronal BDNF release during inflammatory pain. P2RX4 knockout mice; immunofluorescence co-localization; Ca2+ imaging in DRG neurons; western blot for phospho-Erk1/2, phospho-GluN1, KCC2 in spinal cord Scientific reports High 29343707
2018 P2X4R regulates calcium entry and lysosomal exocytosis in hepatic myofibroblasts (hMFs); P2X4 genetic invalidation or pharmacological inhibition blunted hMF activation marker expression and fibrogenic properties and impacted ATP release and profibrogenic secretory profile, placing lysosomal P2X4-mediated calcium and exocytosis upstream of transcription factor activation in liver fibrogenesis. P2X4 KO mice; bile duct ligation and MCD diet models; P2X4 siRNA and pharmacological inhibition; calcium entry assays; lysosomal exocytosis measurement; hMF isolation from mouse and human liver Journal of hepatology High 29802948
2020 Bone marrow plasma cells use P2RX4 to sense extracellular ATP released by osteoblasts through PANX3; P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis—P2RX4 blockade causes accumulation of ER stress-associated proteins ATF4 and CHOP, and B-lineage deletion of the pro-apoptotic ATF4 target Chop prevents bone marrow plasma cell death on P2RX4 inhibition. P2rx4 and Panx3 knockout mice; in vitro osteoblast-plasma cell co-culture; 5-BDBD P2RX4-specific inhibitor; western blot for ATF4, CHOP; B-lineage-specific Chop KO genetic rescue; serum antibody measurement Nature High 38355795
2020 Increased surface density of P2X4 receptors (achieved via internalization-defective P2X4mCherryIN knock-in) alters hippocampal LTP and LTD at CA1 synapses without affecting basal excitatory transmission, and produces anxiolytic effects and spatial memory deficits in mice. Conditional knock-in mice (Floxed P2X4mCherryIN); electrophysiology (LTP/LTD at CA1 synapses); behavioral tests (anxiety, spatial memory) Molecular psychiatry High 31911635
2020 P2X4R activation in renal proximal tubular cells drives NLRP3 inflammasome signaling (NLRP3 and caspase-1 induction, IL-1β processing); P2X4 KO mice showed significantly attenuated NLRP3 inflammasome activation after renal ischemia-reperfusion, and P2X4 agonist ivermectin induced NLRP3 inflammasome activation in human proximal tubule cells. P2X4 KO mice; ischemia-reperfusion model; ATPγS stimulation of isolated renal proximal tubules; 5-BDBD inhibitor; western blot for NLRP3, caspase-1, IL-1β; ivermectin stimulation of human proximal tubule cells FASEB journal High 32086866
2022 Chemotherapy-induced tumor cell death releases ATP that activates P2X4 in neighboring colorectal cancer cells, triggering mTOR-dependent pro-survival signaling via elevated reactive oxygen species and increased DNA damage; P2X4 inhibition or mTOR blockade synergizes with chemotherapy to cause massive ROS-dependent cancer cell death. Patient-derived colorectal tumor organoids; ATP release measurement; P2X4 receptor inhibition; mTOR pathway (S6 phosphorylation) assay; ROS scavenging; combination chemotherapy experiments Nature High 36385525
2023 Cryo-EM structures of zebrafish P2X4 in complex with allosteric antagonists BX430 and BAY-1797 reveal both bind the same allosteric site at subunit interfaces at the top of the extracellular domain; structure-based mutagenesis identified critical residues for allosteric inhibition of both zebrafish and human P2X4. The binding stabilizes a conformation that prevents structural changes of the extracellular domain associated with channel activation. Cryo-EM structure determination; structure-based mutagenesis; electrophysiology validation of mutant effects Nature communications High 37833294
2014 Allosteric modulator ivermectin (IVM) increases efficacy of ATP, slows receptor deactivation and desensitization, and specifically enables transition from open to dilated pore state of rat P2X4R; mutagenesis of vestibular and transmembrane domain residues showed IVM has distinct effects on channel opening versus pore dilation, with pore dilation coupled to receptor re-sensitization that rescues receptors from desensitization. Whole-cell patch clamp of rat P2X4R in HEK293T cells; ivermectin treatment; vestibular and TM domain mutagenesis; Markov state kinetic modeling Pflugers Archiv High 24917516
2016 P2X4 receptor on vascular endothelial cells is required for ischemic preconditioning-mediated neuroprotection; fluid shear stress (mimicking reperfusion) stimulates P2X4, which promotes increased expression of the neuroprotective molecule osteopontin; intracerebroventricular administration of osteopontin recapitulated the neuroprotective effect. P2X4 knockout mice; MCAO model; fluid shear stress stimulation; osteopontin expression measurement; ICV administration of osteopontin Scientific reports Medium 27173846
2021 HCV infection activates a caspase-3/pannexin-1/P2X4 pathway that controls secretion of exosomes and exosomal miRNAs (miR-122, miR-146a) from infected hepatocytes; inhibition of caspase-3, Panx1, or P2X4 each decreased exosome and exosomal miRNA secretion. Inhibition of caspase-3, pannexin-1, and P2X4 in HCV-infected Huh7.5.1 cells; exosome isolation and miRNA quantification Hepatology Medium 34218459
2020 P2X4 and P2X7 channels promote initial Ca2+ microdomains tens of milliseconds after T cell stimulation; pannexin-1-dependent activation of P2X4 occurs in the absence of TCR/CD3 stimulation, and upon TCR stimulation ATP release autocrinally activates both P2X4 and P2X7 to amplify Ca2+ microdomains within the first second of T cell activation. High-resolution Ca2+ live-cell imaging; P2rx4 and P2rx7 knockout T cells; pharmacological inhibition/blocking of P2X4 and P2X7; pannexin-1 dependence assessed Science advances High 35119925
2023 Microglial P2X4 upregulation (increased surface P2X4 in reactive microglia) is required for tactile allodynia and spinal neuron hyperexcitability in neuropathic pain in both male and female mice; global and myeloid-specific P2X4 KO mice both lack these responses, and pharmacological blockade of P2X4 or TrkB relieves tactile allodynia. P2X4mCherryIN knock-in mice; global P2X4KO; myeloid-specific P2X4KO; nerve injury neuropathy model; in vivo electrophysiology; von Frey testing; TrkB pharmacological blockade iScience High 37860691
2012 P2X4 knockdown in RAW264.7 macrophages reduces the initial peak of intracellular Ca2+ after ATP treatment but does not affect P2X7-mediated pore formation or ERK1/2 and p38 MAPK activation; however, P2X4 knockdown significantly suppresses P2X7-dependent macrophage cell death, indicating P2X4 contributes to P2X7-mediated cell death via Ca2+ influx but not pore formation or MAPK signaling. shRNA knockdown of P2X4; Ca2+ imaging; large pore formation assay; ERK1/2 and p38 MAPK phosphorylation western blot; cell viability assay with ATP and BzATP Biochemical and biophysical research communications Medium 22349510
1998 Full-length human P2X4 cDNA encodes a 388-residue protein; injection of full-length but not alternatively spliced cRNA into Xenopus oocytes produces ATP-gated non-selective cation currents, establishing that the alternatively spliced variant (whose first 90 aa are replaced by an hsp-90 homologous sequence) is non-functional as an ion channel. Xenopus oocyte expression; cRNA injection; electrophysiology; in vitro translation; Northern blot; RT-PCR; RNase protection assay Gene Medium 9511769
2022 P2X4 is primarily localized in endolysosomes of breast cancer cells and promotes cancer progression by regulating lysosome acidity, promoting autophagy and cell survival, and driving epithelial-to-mesenchymal transition (EMT); pharmacological and siRNA-mediated inhibition of P2X4 both inhibited autophagy and EMT, and rescue of P2X4 in knocked-down cells restored the aggressive phenotype. P2X4 siRNA knockdown; pharmacological inhibition; rescue experiment; lysosome acidity measurement; autophagy assays; EMT marker expression; in vivo mouse mammary tumor model Oncogene Medium 35411034
2021 Sarcoma patient-derived extracellular vesicle proteins (including Del-1 and SDF-1) trigger trafficking of lysosomal P2XR4 to the cell membrane of endothelial cells, required for cell motility and formation of stable vascular networks; P2XR4 blockade reduced EV-induced vessel formation in angioreactors and intratumor vascularization in mouse xenografts. Proteomics of plasma EVs; Ca2+ mobilization assay; mitochondrial activation assay; P2XR4 surface translocation imaging; P2XR4 antagonist treatment; in vitro angiogenesis and Transwell assays; mouse xenograft angioreactor model Cell death & disease Medium 34404763
2012 P2X4 inhibition (pharmacological blockade) reduced microglial membrane ruffling, TNFα secretion, and morphological changes in LPS-activated microglia in vitro, and prevented LPS-induced microglial cell death in vivo, whereas P2X4 facilitation potentiated LPS-induced microglial loss; P2X4 activity thus controls the fate and survival of activated microglia. Patch-clamp recordings of LPS-activated microglia; P2X4 blockade/facilitation in vitro and in vivo (LPS injection); TNFα ELISA; morphology and survival analysis Glia Medium 24254916

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 253 17299767
1998 Central P2X4 and P2X6 channel subunits coassemble into a novel heteromeric ATP receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 204 9736638
2007 Evidence for functional P2X4/P2X7 heteromeric receptors. Molecular pharmacology 193 17785580
2018 P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO molecular medicine 159 29973381
2017 P2X4: A fast and sensitive purinergic receptor. Biomedical journal 137 29179879
2018 Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. The Journal of clinical investigation 129 29894310
2017 P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology. Frontiers in pharmacology 121 28588493
2013 P2X4 receptors and neuropathic pain. Frontiers in cellular neuroscience 116 24191146
2015 Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion. The Journal of cell biology 112 26101220
2012 N-substituted phenoxazine and acridone derivatives: structure-activity relationships of potent P2X4 receptor antagonists. Journal of medicinal chemistry 91 23075067
2018 Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI insight 90 29875325
2013 P2X4 receptors control the fate and survival of activated microglia. Glia 83 24254916
2005 Biochemical and functional evidence for heteromeric assembly of P2X1 and P2X4 subunits. Journal of neurochemistry 79 15686495
2012 CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic signalling 78 22222817
2018 Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation. Journal of neuroinflammation 77 30165876
2022 Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation. Nature 72 36385525
2020 Neuroprotective and neuro-rehabilitative effects of acute purinergic receptor P2X4 (P2X4R) blockade after ischemic stroke. Experimental neurology 72 32289314
2008 Alteration of purinergic P2X4 and P2X7 receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine. Epilepsy research 72 19084381
2017 Interaction of Purinergic P2X4 and P2X7 Receptor Subunits. Frontiers in pharmacology 70 29213241
2012 Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages. Biochemical and biophysical research communications 70 22349510
2015 Identification and characterization of a selective allosteric antagonist of human P2X4 receptor channels. Molecular pharmacology 69 25597706
2021 Piperine promotes autophagy flux by P2RX4 activation in SNCA/α-synuclein-induced Parkinson disease model. Autophagy 68 34092198
2013 A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of age-related macular degeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 23303206
2020 Contribution of P2X4 Receptors to CNS Function and Pathophysiology. International journal of molecular sciences 63 32756482
2018 Sensory neuronal P2RX4 receptors controls BDNF signaling in inflammatory pain. Scientific reports 60 29343707
2011 P2X4 receptors interact with both P2X2 and P2X7 receptors in the form of homotrimers. British journal of pharmacology 59 21385174
2012 P2X4 purinoceptor signaling in chronic pain. Purinergic signalling 58 22528681
2018 P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia. Molecular pain 57 30146940
2016 Characterization of P2X4 receptor agonists and antagonists by calcium influx and radioligand binding studies. Biochemical pharmacology 53 27867013
2009 Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation. European journal of immunology 53 19283779
2016 P2X4 Receptor Reporter Mice: Sparse Brain Expression and Feeding-Related Presynaptic Facilitation in the Arcuate Nucleus. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 27559172
2022 P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation. Science advances 50 35119925
2012 P2X4 receptor channels form large noncytolytic pores in resting and activated microglia. Glia 50 22318986
2017 Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis. Human mutation 49 28326637
2015 The P2X7/P2X4 interaction shapes the purinergic response in murine macrophages. Biochemical and biophysical research communications 49 26456657
2013 The relationship between P2X4 and P2X7: a physiologically important interaction? Frontiers in physiology 48 23966951
2021 Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective. Frontiers in immunology 47 33897694
2014 Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis. Inflammation 47 24062058
2019 Role of the P2X4 receptor in neuropathic pain. Current opinion in pharmacology 46 30878800
2017 Ethanol differentially modulates P2X4 and P2X7 receptor activity and function in BV2 microglial cells. Neuropharmacology 45 28943285
2015 Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization. Journal of the American Society of Nephrology : JASN 45 26160898
2014 P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Frontiers in neuroscience 45 25009459
2024 Bone marrow plasma cells require P2RX4 to sense extracellular ATP. Nature 44 38355795
2016 P2rx4 deficiency in mice alleviates allergen-induced airway inflammation. Oncotarget 44 27863396
2007 P2X1 and P2X4 receptor currents in mouse macrophages. British journal of pharmacology 44 17934511
2017 P2X4 Receptor-Dependent Ca2+ Influx in Model Human Monocytes and Macrophages. International journal of molecular sciences 43 29077063
2020 P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 32086866
2022 P2x4 receptor promotes mammary cancer progression by sustaining autophagy and associated mesenchymal transition. Oncogene 39 35411034
2012 Imaging P2X4 receptor lateral mobility in microglia: regulation by calcium and p38 MAPK. The Journal of biological chemistry 39 22393055
2002 P2X4 receptor is a glycosylated cardiac receptor mediating a positive inotropic response to ATP. The Journal of biological chemistry 39 11864978
2022 P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice. Neuroscience bulletin 38 35254644
2020 Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice. Molecular psychiatry 38 31911635
2020 The role of P2X4 receptors in chronic pain: A potential pharmacological target. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 32887026
2019 P2X4 and lysosome fusion. Current opinion in pharmacology 38 31039505
2016 The P2X4 receptor is required for neuroprotection via ischemic preconditioning. Scientific reports 38 27173846
2019 Targeting P2X4 and P2X7 receptors in multiple sclerosis. Current opinion in pharmacology 37 31015145
2013 Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats. Frontiers in physiology 37 24187541
2014 Imaging P2X4 receptor subcellular distribution, trafficking, and regulation using P2X4-pHluorin. The Journal of general physiology 36 24935743
2014 P2X4 receptor regulates alcohol-induced responses in microglia. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 36 25135400
2022 The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target. International journal of molecular sciences 35 35628550
2020 Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders. Neuroscience bulletin 34 32889635
2004 Expression of P2X4 receptor in rat C6 glioma by tumor-associated macrophages and activated microglia. Journal of neuroimmunology 34 15223238
1998 The human P2X4 receptor gene is alternatively spliced. Gene 34 9511769
2023 Structural insights into the allosteric inhibition of P2X4 receptors. Nature communications 33 37833294
2021 P2X4 purinergic receptors offer a therapeutic target for aggressive prostate cancer. The Journal of pathology 33 34652816
2020 The role of P2X4 receptor in neuropathic pain and its pharmacological properties. Pharmacological research 33 32407956
2019 P2X4 receptors, immunity, and sepsis. Current opinion in pharmacology 32 30921560
2014 P2X4 receptors expressed on microglial cells in post-ischemic inflammation of brain ischemic injury. Neurochemistry international 32 24486458
2020 Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target. Cells 30 33233569
2013 Carbamazepine derivatives with P2X4 receptor-blocking activity. Bioorganic & medicinal chemistry 30 24411477
2022 Pinocembrin Inhibits P2X4 Receptor-Mediated Pyroptosis in Hippocampus to Alleviate the Behaviours of Chronic Pain and Depression Comorbidity in Rats. Molecular neurobiology 29 36088500
2020 Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation. Journal of immunology (Baltimore, Md. : 1950) 29 32358018
2014 P2X4 receptor regulation of transient receptor potential melastatin type 6 (TRPM6) Mg2+ channels. Pflugers Archiv : European journal of physiology 29 24413910
2012 Expression of P2X₁ and P2X₄ receptors in rat trigeminal ganglion neurons. Neuroreport 29 22785548
2018 Ginsenosides Act As Positive Modulators of P2X4 Receptors. Molecular pharmacology 28 30545933
2021 Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients. Cell death & disease 27 34404763
2020 Contribution of the P2X4 Receptor in Rat Hippocampus to the Comorbidity of Chronic Pain and Depression. ACS chemical neuroscience 27 33284579
2018 The P2X4 purinergic receptor regulates hepatic myofibroblast activation during liver fibrogenesis. Journal of hepatology 27 29802948
2020 Dissection of P2X4 and P2X7 Receptor Current Components in BV-2 Microglia. International journal of molecular sciences 26 33187309
2019 Dexmedetomidine attenuates P2X4 and NLRP3 expression in the spine of rats with diabetic neuropathic pain. Acta cirurgica brasileira 26 31859818
2021 The Pannexin 1/Purinergic Receptor P2X4 Pathway Controls the Secretion of MicroRNA-Containing Exosomes by HCV-Infected Hepatocytes. Hepatology (Baltimore, Md.) 25 34218459
2014 Immunolocalization of the P2X4 receptor on neurons and glia in the mammalian retina. Neuroscience 24 24997270
2011 Pharmacologically targeting the P2rx4 gene on maintenance and reinstatement of alcohol self-administration in rats. Pharmacology, biochemistry, and behavior 24 21402096
2009 P2X2, P2X4 and P2Y1 receptors elevate intracellular Ca2+ in mouse embryonic stem cell-derived GABAergic neurons. British journal of pharmacology 24 20050186
2015 Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats. Alcoholism, clinical and experimental research 23 26334550
2023 Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice. iScience 22 37860691
2019 Dopamine Receptor Blockade Attenuates Purinergic P2X4 Receptor-Mediated Prepulse Inhibition Deficits and Underlying Molecular Mechanisms. Frontiers in cellular neuroscience 22 31396053
2014 Allosteric regulation of the P2X4 receptor channel pore dilation. Pflugers Archiv : European journal of physiology 22 24917516
2004 Enhanced expression of the P2X4 receptor in Duchenne muscular dystrophy correlates with macrophage invasion. Neurobiology of disease 22 15006691
2021 P2X4 receptor participates in autophagy regulation in Parkinson's disease. Neural regeneration research 21 33907041
2014 Exaggerated renal fibrosis in P2X4 receptor-deficient mice following unilateral ureteric obstruction. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 21 24574541
2013 P2X4 promotes interleukin‑1β production in osteoarthritis via NLRP1. Molecular medicine reports 21 24145861
2022 Role of P2X4/NLRP3 Pathway-Mediated Neuroinflammation in Perioperative Neurocognitive Disorders. Mediators of inflammation 20 35153623
2022 Activation of P2X4 receptor exacerbates acute brain injury after intracerebral hemorrhage. CNS neuroscience & therapeutics 20 35352488
2020 Functional expression of P2X1, P2X4 and P2X7 purinergic receptors in human monocyte-derived macrophages. European journal of pharmacology 20 32805257
2010 Structural insights into the function of P2X4: an ATP-gated cation channel of neuroendocrine cells. Cellular and molecular neurobiology 20 21107680
2020 Deviant reporter expression and P2X4 passenger gene overexpression in the soluble EGFP BAC transgenic P2X7 reporter mouse model. Scientific reports 19 33199725
2020 P2Y2 and P2X4 Receptors Mediate Ca2+ Mobilization in DH82 Canine Macrophage Cells. International journal of molecular sciences 19 33202978
2021 The mechanism by which ATP regulates alcoholic steatohepatitis through P2X4 and CD39. European journal of pharmacology 18 34973190
2012 Fluvastatin suppresses native and recombinant human P2X4 receptor function. Purinergic signalling 18 22222818

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