Affinage

P2RY4

P2Y purinoceptor 4 · UniProt P51582

Length
365 aa
Mass
41.0 kDa
Annotated
2026-06-10
92 papers in source corpus 37 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RY4 (P2Y4) is a pyrimidinergic G-protein-coupled receptor that couples to phospholipase C to generate inositol trisphosphate and mobilize intracellular Ca2+ in response to extracellular nucleotides (PMID:8997625). UTP is the primary full agonist of the human receptor, where ATP behaves as a competitive antagonist, whereas the rodent orthologs are activated equipotently by UTP and ATP — a species difference traced to residues in the second extracellular loop and N-terminus (including Asn-177/Y197) that govern ATP agonism versus antagonism (PMID:10779375, PMID:14670966, PMID:31812541). The receptor is pharmacologically distinguished from other P2Y subtypes by its insensitivity to suramin and PPADS (PMID:8968535, PMID:9647463, PMID:9751165). Beyond Gq/PLC, P2Y4 engages Gi/o (pertussis-toxin-sensitive) coupling, RhoA/Rho-kinase-driven actin remodeling, PI3K/Akt, and ERK/p38/JNK MAPK cascades that drive proliferation and immediate-early/AP-1 transcription (PMID:8997625, PMID:10843869, PMID:15649700, PMID:24001770). Signaling is terminated by agonist-promoted phosphorylation of carboxy-terminal Ser-333/Ser-334, which mediates desensitization and internalization (PMID:11114308), and the receptor is delivered to the apical membrane of polarized epithelia by an autonomous hydrophobic 23-residue C-terminal sorting signal (PMID:23054062). P2Y4 assembles into homo-oligomers and selective hetero-oligomers with P2Y6, and co-localizes with NMDAR1 (PMID:18404459, PMID:17481575, PMID:15383322). Functionally, it couples to M-type K+ and N-type Ca2+ channels and to Ca2+-activated K+ channels in neurons and heterologous systems (PMID:12540532, PMID:16075244), and is required in vivo for nucleotide-regulated epithelial Cl-, K+, and Na+ transport (PMID:12644577, PMID:15718265, PMID:16056234, PMID:20220010). P2Y4-null mice further reveal roles in postnatal cardiac growth via endothelial PDGF-B signaling (PMID:22437266), in post-ischemic cardiac inflammation through an ET-1/PD-L1/exosome and adiponectin axis (PMID:25595790, PMID:36248854, PMID:41164751), and in glucose homeostasis, where the human loss-of-function N178T variant and adiponectin-dependent epistasis link the receptor to insulin sensitivity (PMID:36532779, PMID:27855539).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established the molecular identity and signaling output of P2Y4 — that the cloned receptor is a UTP-preferring pyrimidinergic GPCR coupling to PLC, resolving its place among purinoceptors.

    Evidence Genomic cloning, tissue Northern/RT-PCR, and stable expression in 1321N1 cells with IP accumulation and pertussis toxin block

    PMID:8617367 PMID:8968535 PMID:8997625

    Open questions at the time
    • Dual Gq/Gi coupling inferred from PTX block only, no direct G-protein reconstitution
    • Endogenous tissue function not addressed
  2. 1998 High

    Defined a species-specific pharmacology — rodent P2Y4 is activated equipotently by ATP and UTP while human P2Y4 is not — a distinction critical for interpreting all cross-species functional studies.

    Evidence Rat genomic cloning and pharmacological characterization in transfected and native aortic smooth muscle cells, with MAPK and proliferation readouts

    PMID:9647463 PMID:9690862 PMID:9751165

    Open questions at the time
    • Structural basis of species difference not yet localized
    • Physiological relevance of smooth-muscle proliferation untested in vivo
  3. 2000 High

    Quantified the ATP antagonism at human P2Y4 and identified Ser-333/Ser-334 phosphorylation as the desensitization/internalization switch, defining how receptor activity is terminated.

    Evidence Schild analysis of Ca2+ responses in 1321N1 cells; truncation/point mutagenesis with 32P radiolabeling and surface receptor quantitation; RhoA dominant-negative and C3 exoenzyme assays

    PMID:10779375 PMID:10843869 PMID:11114308

    Open questions at the time
    • Kinase responsible for Ser-333/334 phosphorylation not identified
    • Arrestin/clathrin machinery of internalization not defined
  4. 2003 High

    Localized the determinants of ATP agonism to EL2/N-terminus and showed P2Y4 controls neuronal ion channels, linking receptor structure to effector coupling.

    Evidence Human/rat chimeric and point mutagenesis with Ca2+ assays; electrophysiological reconstitution in rat sympathetic neurons with PTX and transducin Gα

    PMID:12540532 PMID:14670966

    Open questions at the time
    • Full orthosteric pocket structure not resolved
    • Endogenous neuronal agonist source unaddressed
  5. 2003 Medium

    Demonstrated that P2Y4 self-assembles into disulfide-linked homo-oligomers, raising the question of oligomerization-dependent function.

    Evidence Differential co-immunoprecipitation of tagged constructs; reducing/non-reducing SDS-PAGE

    PMID:18404459

    Open questions at the time
    • Functional consequence of oligomerization not established
    • Single lab
  6. 2005 High

    Genetic knockout established P2Y4 as the essential receptor for nucleotide-regulated epithelial Cl- and K+ transport in intestine, moving from heterologous pharmacology to physiological necessity.

    Evidence P2Y4-null, P2Y2-null, and double-KO mice with Ussing-chamber short-circuit current; Xenopus oocyte co-expression with BK/IK channels

    PMID:12644577 PMID:15718265 PMID:16056234 PMID:16075244

    Open questions at the time
    • Coupling between receptor and specific channels in native epithelium correlative
    • Apical channel identity in vivo not fully resolved
  7. 2005 Medium

    Showed P2Y4 drives neuronal differentiation and immediate-early/AP-1 transcription, extending its role beyond ion transport into developmental gene programs.

    Evidence Transfection of SH-SY5Y cells with UTP stimulation; morphology, NFL immunostaining, RT-PCR for cdk-5/NeuroD6, AP-1 reporters

    PMID:15649700

    Open questions at the time
    • Performed in overexpression system
    • Endogenous neuronal contribution not isolated
  8. 2007 Medium

    Refined oligomerization biology by showing endogenous P2Y4 forms selective P2Y6 hetero-oligomers and partitions into lipid rafts in native neurons.

    Evidence Blue Native PAGE, co-IP, and lipid raft fractionation from synaptosomes and PC12 cells

    PMID:17481575

    Open questions at the time
    • Signaling output of P2Y4/P2Y6 heteromers not determined
    • Single lab
  9. 2012 Medium

    Defined the apical-sorting signal and established a developmental cardiac function, connecting receptor trafficking and endothelial signaling to postnatal heart growth.

    Evidence Mutagenesis/chimera localization in polarized MDCK/Caco-2 cells; P2Y4-null mice with endothelial proliferation, migration, and PDGF-B assays

    PMID:22437266 PMID:23054062

    Open questions at the time
    • Trafficking machinery recognizing the hydrophobic signal unidentified
    • Endothelial-cardiomyocyte crosstalk mechanism correlative
  10. 2013 Medium

    Showed P2Y4 drives microglial pinocytosis via PI3K/Akt, implicating it in nucleotide-driven uptake including amyloid-beta.

    Evidence siRNA knockdown and PI3K/Akt inhibitors with fluorescence pinocytosis assay

    PMID:24001770

    Open questions at the time
    • Direct receptor-to-PI3K coupling not biochemically mapped
    • In vivo relevance untested
  11. 2016 Medium

    Placed adiponectin downstream of P2Y4 in cardiac adipogenesis and identified a role in glutamatergic neuron specification, broadening the receptor's developmental and metabolic reach.

    Evidence P2Y4-null and P2Y4/adiponectin double-KO epistasis with adipogenic and adiponectin assays; ESC/NSC differentiation with P2Y4 pharmacology and vGluT/TBR1 staining

    PMID:26972684 PMID:27855539

    Open questions at the time
    • Mechanism linking receptor to adiponectin transcription unresolved
    • Neuronal specification shown pharmacologically, no genetic NSC deletion
  12. 2019 Medium

    Implicated P2Y4 in neuroinflammation, showing HIV-1 Tat upregulates the receptor and P2Y4 signaling drives cytokine production via PI3K/Akt and ERK.

    Evidence siRNA knockdown in vitro and in vivo, pathway inhibitors, cytokine and apoptosis readouts

    PMID:30947729

    Open questions at the time
    • Direct receptor-Tat relationship not biochemically defined
    • Single lab
  13. 2022 Medium

    Mapped the cardioprotective consequences of P2Y4 loss to PD-L1- and adiponectin-dependent anti-inflammatory pathways, and characterized a human loss-of-function variant linking the receptor to glucose homeostasis.

    Evidence P2Y4-null mice with LAD ligation, flow cytometry, anti-PD-L1 blockade epistasis; N178T variant Ca2+ assay and P2Y4/adiponectin double-KO glucose tolerance tests

    PMID:36248854 PMID:36532779

    Open questions at the time
    • PD-L1 and adiponectin placed downstream by epistasis but direct transcriptional control not shown
    • Human variant phenotype based on rodent mechanism
  14. 2025 Medium

    Integrated the cardioprotection axis into an exosome-mediated mechanism, showing PD-L1+ and adiponectin-associated exosomes from P2Y4-null adipose tissue polarize macrophages and reduce fibrosis.

    Evidence P2Y4-null mice with GW4869 exosome-inhibitor epistasis, nanoparticle tracking, TEM, CDH13 Western blot, in vitro macrophage polarization

    PMID:41164751

    Open questions at the time
    • Causal chain from receptor to exosome biogenesis correlative
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How agonist binding is structurally transduced to selective G-protein, channel, and oligomer-dependent outputs, and whether the ET-1/PD-L1/adiponectin/exosome cardiac axis operates in humans, remain unresolved.
  • No experimental receptor structure
  • Human in vivo cardiac/metabolic mechanism rests on rodent KO inference
  • Kinase and trafficking machinery for desensitization and apical sorting unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
GRIN1P2RY6

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Human P2Y4 receptor, stably expressed in 1321N1 astrocytoma cells, functions as a pyrimidinergic GPCR that couples to phospholipase C to produce inositol trisphosphates. UTP is the primary full agonist; ATP acts as a pure antagonist at early times and partial agonist later. Pertussis toxin inhibited the early UTP response (~62%), suggesting the receptor can couple to both Gi/o and Gq proteins in a time-dependent manner. Stable transfection in 1321N1 cells; inositol phosphate accumulation assay; pertussis toxin treatment European journal of pharmacology High 8997625
1996 Human P2Y4 receptor (cloned as P2P) is encoded by an intronless single-copy gene, expressed predominantly in pancreas, and encodes a 365 amino acid GPCR with high structural homology to P2U/P2Y purinoceptors within transmembrane domains. Genomic cloning, Northern blot, RT-PCR tissue distribution FEBS letters Medium 8617367
1996 Human P2Y4 receptor is not antagonized by suramin or PPADS (unlike P2Y1 and P2Y2), defining a pharmacologically distinct profile among cloned P2Y receptors when stably expressed in 1321N1 cells. Stable transfection in 1321N1 cells; pharmacological antagonism assays British journal of pharmacology High 8968535
1998 Rat P2Y4 receptor (rP2Y4), unlike the human ortholog, is activated equipotently by both ATP and UTP (partial agonists: ADP, ATPγS, 2-MeSATP, UDP), making it pharmacologically similar to the P2U receptor subtype but suramin-insensitive (distinguishing it from P2Y2). The receptor is reversibly antagonized by Reactive Blue 2. Rat genomic library cloning; expression and pharmacological characterization in transfected cells British journal of pharmacology High 9647463 9751165
1998 P2Y4 receptor mediates phospholipase C responses to extracellular UTP and ATP in spontaneously hypertensive rat aortic smooth muscle cells. ATP behaves as a partial agonist compared to UTP; UDP response is abolished by hexokinase, consistent with conversion to UTP. P2Y4 mRNA was confirmed by RT-PCR in these cells. Stimulation activates p42/p44 MAPK, which in turn drives thymidine incorporation (proliferation). RT-PCR; PLC assay; hexokinase competition; MAPK phosphorylation assay; [3H]-thymidine incorporation; comparison with 1321N1 cells transfected with hP2Y4 British journal of pharmacology Medium 9690862
2000 ATP is a competitive antagonist (pA2 = 6.15) at the human P2Y4 receptor but a potent full agonist at the rat P2Y4 receptor, demonstrating a species-specific difference in agonist/antagonist behavior at this receptor. CTP and Ap4A were partial antagonists at hP2Y4. Stable expression in 1321N1 cells; intracellular Ca2+ measurement under conditions minimizing nucleotide metabolism; Schild plot analysis Molecular pharmacology High 10779375
2000 P2Y4 receptor (along with P2Y1, P2Y2, P2Y6) couples to RhoA activation and subsequent Rho kinase-dependent actin stress fiber formation in vascular myocytes. Dominant-negative RhoA and C3 exoenzyme blocked this response. Transfection of P2Y4 into Swiss 3T3 cells confirmed Rho kinase-dependent actin reorganization. Dominant-negative RhoA transfection; C3 exoenzyme treatment; Y-27632 Rho kinase inhibition; membrane-bound RhoA quantitation; Swiss 3T3 cell transfection American journal of physiology. Heart and circulatory physiology Medium 10843869
2000 Agonist-promoted phosphorylation of human P2Y4 receptor at Ser-333 and Ser-334 in the carboxyl terminus mediates UTP-dependent desensitization and internalization (50% loss of surface receptors). Truncation and point mutagenesis identified these residues as essential; the P2Y4-332 truncation mutant showed no UTP-promoted [32P] phosphorylation. In contrast, P2Y6 receptor does not undergo rapid agonist-dependent desensitization or internalization. Mutagenesis (truncation and point mutations); [32P]Pi radiolabeling; surface receptor quantitation; inositol phosphate desensitization assay in 1321N1 cells The Journal of biological chemistry High 11114308
2001 Mouse P2Y4 receptor is equally activated by UTP and ATP (like rat P2Y4), is antagonized by PPADS and Reactive Blue 2, and is not blocked by suramin — confirming the rodent P2Y4 pharmacological profile. mRNA detected in liver, intestine, stomach, bladder, and lung. Mouse genomic library screening; stable expression in 1321N1 cells; pharmacological characterization European journal of pharmacology Medium 11290369
2001 P2Y4 receptor at the apical membrane of vestibular dark cell epithelium mediates inhibition of K+ secretion (electrogenic short-circuit current) by UTP, ATP, and diadenosine tetraphosphate but not UDP. Insensitivity to suramin (100 µM) supports P2Y4 identity. The response showed no desensitization over 15 min of sustained agonist exposure. Voltage-sensitive vibrating probe (electrophysiology); RT-PCR for P2Y2/P2Y4; pharmacological profiling with antagonists American journal of physiology. Cell physiology Medium 11401851
2002 P2Y4 receptor protein is immunolocalized specifically to the apical membrane of strial marginal cells and vestibular dark cells in the gerbil inner ear, while P2Y2 is located basolaterally. Western blot detected a 55 kDa band in stria vascularis for P2Y4. Western blot; fluorescence confocal immunohistochemistry; peptide blocking controls The Journal of membrane biology Medium 11891569
2003 P2Y4-null mice generated by gene targeting completely lack UTP- and ATP-induced chloride secretion in the jejunum (measured as short-circuit current in Ussing chambers), demonstrating that P2Y4 is required for nucleotide-regulated epithelial chloride transport in the small intestine. Gene targeting knockout; Ussing chamber short-circuit current measurement; RT-PCR confirmation of mRNA loss Molecular pharmacology High 12644577
2003 The second extracellular loop (EL2) and NH2-terminus of P2Y4 receptor together form a functional motif determining whether ATP acts as an agonist or antagonist. Chimeric receptor analysis and mutagenesis identified three specific residues in EL2 (Asn-177, Ile-183, Leu-190 in hP2Y4) as key determinants of ATP agonism. Replacement of hP2Y4 EL2 with rP2Y4 EL2 converted ATP from antagonist to near-full agonist. Human/rat P2Y4 chimeric receptor expression in 1321N1 cells; point mutagenesis; intracellular Ca2+ assay The Journal of biological chemistry High 14670966
2003 Human and rat P2Y4 receptors, expressed in rat sympathetic neurons, couple to M-type K+ channels (IC50 ~21–28 nM for UTP) and to N-type Ca2+ channels (IC50 ~273 nM). Ca2+ channel inhibition requires a diffusible intracellular factor lost in ruptured-patch recording and involves Gβγ subunits of Gi/o proteins (blocked by pertussis toxin and transducin Gα). M-current inhibition is PTX-insensitive. P2Y4 couples more effectively to M-type K+ channels than to Ca2+ channels. Nuclear injection of P2Y4 cDNA into rat sympathetic neurons; whole-cell and perforated-patch electrophysiology; PTX pretreatment; transducin Gα co-expression British journal of pharmacology High 12540532
2003 P2Y4 receptor forms homo-dimers and higher-order oligomeric complexes, at least partially assembled through disulfide bonds. Co-transfection with differentially tagged P2Y4 constructs followed by differential co-immunoprecipitation directly demonstrated homodimerization. Co-transfection with differentially tagged receptors; co-immunoprecipitation; SDS-PAGE under reducing/non-reducing conditions Purinergic signalling Medium 18404459
2004 Co-localization of P2Y4 and NMDAR1 receptors at the membrane was demonstrated by confocal double immunofluorescence and confirmed by co-immunoprecipitation in cerebellar granule neurons and HEK-293 cells. During hypoglycemia, P2Y4 expression is induced while NMDAR1 is inhibited; both P2 and NMDA antagonists restore basal expression levels. Co-immunoprecipitation; confocal double immunofluorescence; Western blot during glucose deprivation Experimental cell research Medium 15383322
2005 P2Y4 receptor activation by UTP in neuroblastoma SH-SY5Y cells facilitates neuritogenesis (detected by morphological analysis and neurofilament NFL immunostaining), increases transcription of differentiation-linked genes (cdk-5, NeuroD6) and activates AP-1 family transcription factors (c-fos, fos-B, jun-D). Prolonged P2Y4 activation also induces cell death. Transient transfection; morphological phase contrast and confocal microscopy; RT-PCR for immediate-early genes; cytofluorimetric DNA damage assay; AP-1 reporter assays Neurobiology of disease Medium 15649700
2005 Both P2Y2 and P2Y4 receptors present on the luminal membrane of mouse distal colonic mucosa mediate K+ secretion (measured as transepithelial voltage change and blocked by Ba2+ and iberiotoxin). In P2Y2 KO and P2Y4 KO mice the UTP-stimulated K+ secretion was each significantly reduced; in P2Y2/P2Y4 double KO mice it was completely abolished. P2Y2-null and P2Y4-null and double-knockout mice; Ussing chamber electrophysiology; Ba2+ and iberiotoxin (BK channel) blockers; RT-PCR of isolated crypts The Journal of physiology High 15718265
2005 P2Y4 receptor at the apical membrane of gerbil strial marginal cells mediates UTP/ATP-induced decrease in K+ secretion via PLC activation and biphasic intracellular Ca2+ elevation (partially blocked by 2-APB, an IP3R/SOC inhibitor). Suramin (100 µM) was without effect, consistent with P2Y4 identity. Short-circuit current measurement with voltage-sensitive probe; intracellular Ca2+ imaging; 2-APB pharmacology; RT-PCR for P2Y subtypes Cell communication and signaling : CCS Medium 16266433
2005 P2Y4 receptor (not P2Y2) fully mediates chloride secretory response to UTP in mouse colon (both apical and basolateral sides) and in jejunum (apical side). P2Y4-null mice showed abolished colonic chloride secretion to UTP, whereas P2Y2-null mice were unaffected in the colon. The UTP-potentiated forskolin response was also abolished in P2Y4-null jejunum. P2Y2-null and P2Y4-null knockout mice; Ussing chamber short-circuit current; chloride-free medium control; amiloride/phloridzin controls British journal of pharmacology High 16056234
2005 P2Y4 receptor co-expressed with BK channels in Xenopus oocytes leads to a ~30% increase in BK current upon UTP stimulation, while P2Y2 co-expressed with BK channels causes ~20% inhibition. Co-expression of P2Y4 with IK channels produces a large 22-fold UTP-stimulated current activation. This demonstrates differential regulation of Ca2+-activated K+ channels by P2Y4 vs P2Y2 subtypes. Xenopus oocyte co-expression; electrophysiological recording of K+ channel activity; UTP stimulation Pflugers Archiv : European journal of physiology Medium 16075244
2007 In native neuronal cells, P2Y4 receptor forms high-order oligomeric complexes detectable by Blue Native gel electrophoresis. Dimeric P2Y4 selectively partitions into lipid rafts in synaptosomes. UTP stimulation does not shift P2Y4 oligomerization state (in contrast to P2Y6). In naive PC12 cells, endogenous P2Y4 forms hetero-oligomers selectively with P2Y6 (not with P2Y1, P2Y2, or P2Y11). Blue Native gel electrophoresis; co-immunoprecipitation; lipid raft fractionation from synaptosomes; co-transfection studies Biochimica et biophysica acta Medium 17481575
2008 ATP stimulates excitability of guinea pig gallbladder smooth muscle via P2Y4 receptors (RT-PCR confirmed P2Y4 but not P2Y2 expression in muscularis). This excitation requires COX-1 activity (blocked by indomethacin and SC-560) but not COX-2, indicating P2Y4 stimulates prostanoid production via COX-1 to increase smooth muscle excitability. Intracellular recording (membrane potential and action potential frequency); RT-PCR; pharmacological inhibitors (suramin, PPADS, indomethacin, SC-560, nimesulide) American journal of physiology. Gastrointestinal and liver physiology Medium 18436624
2009 ATP modulates ERK1/2, p38, and JNK1 MAPKs and transcription factors (ATF-1, c-Fos, c-Jun, Jun D) via P2Y2 and P2Y4 receptors in MCF-7 breast cancer cells through a PKC-dependent (not Src-dependent) pathway for MAPK activation. PKC and Src both contribute to c-Fos induction and ATF-1 phosphorylation. RT-PCR receptor identification; specific kinase inhibitors; Src antisense oligonucleotides; Western blot for phospho-MAPKs and transcription factors Archives of biochemistry and biophysics Low 19900397
2010 P2Y4 receptor at the apical membrane of Reissner's membrane epithelium mediates UTP-induced inhibition of amiloride-sensitive Na+ absorption (ENaC) via PLC activation and reduction of plasma membrane PIP2 (not through PKC or store-operated channels). PLC inhibitors markedly reduced the effect; the P2Y4 subtype identity was confirmed by suramin/PPADS insensitivity and RB-2 sensitivity. Voltage-sensitive vibrating probe; amiloride short-circuit current; PLC inhibitors (U73122, ET-18-OCH3); PKC modulators; 2-APB; immunohistochemistry The Journal of neuroscience Medium 20220010
2012 P2Y4 receptor is expressed in cardiac endothelial cells but not cardiomyocytes. P2Y4-null mice display microcardia due to reduced endothelial cell proliferation, migration, and PDGF-B secretion in response to UTP. Microvessel and cardiomyocyte proliferation is reduced early postnatally in P2Y4-null hearts, establishing P2Y4 as a regulator of postnatal cardiac growth through endothelial-cardiomyocyte interactions. P2Y4-null mice; cardiac endothelial cell isolation; proliferation and migration assays; PDGF-B secretion measurement; histological quantitation of cardiomyocyte and microvessel density Angiogenesis Medium 22437266
2012 Apical targeting of P2Y4 receptor to the apical membrane of polarized epithelial cells is directed by a 23 amino acid sequence in the C-terminal cytoplasmic tail. Four hydrophobic residues near the COOH-terminal end are necessary for apical sorting; mutation of these residues results in basolateral enrichment. The signal is autonomous: it can redirect the normally basolateral P2Y12 receptor to the apical membrane. Mutagenesis (truncation and point mutations); confocal immunofluorescence in polarized MDCK/Caco-2 cells; chimeric P2Y4/P2Y12 receptor constructs American journal of physiology. Cell physiology High 23054062
2013 P2Y4 receptor mediates ATP-triggered pinocytosis in microglia via the PI3K/Akt signaling cascade. siRNA knockdown of P2Y4 reduced nucleotide-induced pinocytosis. Soluble amyloid-beta 1-42 induced self-uptake in microglia through pinocytosis involving autocrine ATP signaling activating P2Y4 receptors. P2Y4 siRNA knockdown; pharmacological analysis; PI3K/Akt inhibitors; fluorescence-based pinocytosis assay Molecular and cellular biology Medium 24001770
2015 P2Y4-null mice display smaller myocardial infarcts, reduced neutrophil infiltration, and reduced fibrosis after LAD ligation. Gene profiling identified endothelin-1 (ET-1) as a target gene of P2Y4 in ischemic heart. Loss of P2Y4 is correlated with reduced endothelial cell number, reduced ET-1, reduced MMP-9 and MMP-8 expression, and reduced microvascular hyperpermeability and endothelial adhesion molecule expression. P2Y4-null mice; LAD ligation model; gene expression profiling; immunohistochemistry for neutrophils; ET-1 measurement; MMP/TIMP expression analysis; LPS-induced inflammation model Journal of immunology Medium 25595790
2016 P2Y4 receptor expressed in cardiac adipose-derived stem cells acts as a negative regulator of adipogenic differentiation and cardiac fat formation. UTP (P2Y4 ligand) inhibited maturation of differentiated cardiac ASCs and reduced adipogenesis-linked gene expression and adiponectin secretion. P2Y4-null mice had higher cardiac adipose tissue mass and higher adiponectin secretion. Cardioprotection from P2Y4 loss was absent in P2Y4/adiponectin double-KO mice, placing adiponectin downstream of P2Y4 in this pathway. P2Y4-null mice; adipogenic differentiation assays; gene expression (RT-PCR); adiponectin secretion measurement; double-KO epistasis (P2Y4 x adiponectin); LAD ligation Stem cells and development Medium 27855539
2016 P2Y4 receptor in neural precursors promotes specification of glutamatergic neuron identity. Transient P2Y4 activation during ESC neuronal differentiation increased proportion of neurons expressing vGluT (glutamatergic marker). A subpopulation of adult hippocampal type 2 NSCs expresses P2Y4; its activation induced vGluT and TBR1 expression in descendant neurons. Inhibition of P2Y4 signaling abolished these effects. Mouse ESC differentiation assay; P2Y4 pharmacological activation/inhibition; immunostaining for vGluT and TBR1; adult hippocampal NSC analysis Stem cell reports Medium 26972684
2019 HIV-1 Tat protein increases P2Y4 receptor expression in astrocytes. P2Y4 signaling mediates Tat-induced proinflammatory cytokine production via PI3K/Akt and ERK1/2-dependent pathways. siRNA knockdown of P2Y4 reduced cytokine production and relieved Tat-mediated neuronal apoptosis in vitro. In vivo Tat challenge in P2Y4 knockdown mice showed decreased hippocampal inflammation and neuronal damage. siRNA knockdown; real-time PCR; Western blot; cytometric bead array; TUNEL/MTT assays; in vivo P2Y4 knockdown mouse model; PI3K/Akt/ERK pathway inhibitors Journal of neuroinflammation Medium 30947729
2019 Mutagenesis combined with homology modeling showed that the orthosteric binding site of P2Y4 receptor is more restricted than that of P2Y2. Mutation of Y197 to alanine in P2Y4 receptor conferred gain of ATP sensitivity, identifying this residue as a key determinant of ATP selectivity. Anthraquinone antagonists likely bind orthosteric or allosteric sites depending on their substitution pattern. Site-directed mutagenesis; receptor homology modeling; docking studies; functional Ca2+ assay in transfected 1321N1 cells Biochimica et biophysica acta. General subjects Medium 31812541
2022 P2Y4-null mice display anti-inflammatory pericardial adipose tissue changes after myocardial infarction, including adipocyte beiging with increased PD-L1 expression, higher regulatory M2c macrophages and Treg cells. Injection of anti-PD-L1 blocking antibody abolished the reduction in T cell infiltration and cardiac fibrosis in P2Y4-null ischemic mice, placing PD-L1 downstream of P2Y4 loss in cardioprotection. P2Y4-null mice; LAD ligation; flow cytometry (M2c macrophages, Tregs); anti-PD-L1 antibody blockade epistasis; PD-L1 expression assay Frontiers in immunology Medium 36248854
2022 The N178T variant (rs3745601, second extracellular loop) of human P2Y4 is a loss-of-function mutation. P2Y4-null mice showed improved glucose tolerance and insulin sensitivity; this improvement was absent in P2Y4/adiponectin double-KO mice, placing adiponectin downstream of P2Y4 in glucose homeostasis regulation. Functional Ca2+ assay of N178T variant in transfected cells; P2Y4-null mice glucose tolerance test and insulin sensitivity test; P2Y4/adiponectin double-KO mice Frontiers in pharmacology Medium 36532779
2025 P2Y4-null ischemic mice show increased plasma PD-L1+ exosomes and adiponectin-associated exosomes from adipocyte origin. Inhibition of exosome release (GW4869) abolished the reduction in cardiac fibrosis and T cell infiltration observed in P2Y4-null mice and prevented plasma PD-L1 increase. P2Y4-null pericardial adipose tissue showed increased CDH13/T-cadherin expression (required for adiponectin-driven exosome biogenesis). Exosomes from P2Y4-null ischemic mice polarized macrophages to anti-inflammatory M2c phenotype in vitro. P2Y4-null mice; GW4869 exosome inhibitor treatment epistasis; nanoparticle tracking analysis; TEM; Western blot (CD63, adiponectin); flow cytometry (PD-L1+ exosomes); in vitro macrophage polarization assay Frontiers in pharmacology Medium 41164751

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 187 16000618
1998 Molecular cloning and characterization of rat P2Y4 nucleotide receptor. British journal of pharmacology 161 9647463
1996 Pharmacological characterization of the human P2Y4 receptor. European journal of pharmacology 130 8997625
2003 Extended pharmacological profiles of rat P2Y2 and rat P2Y4 receptors and their sensitivity to extracellular H+ and Zn2+ ions. British journal of pharmacology 125 14581177
2003 Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochemistry and cell biology 115 14564529
1998 Molecular cloning and characterization of the rat P2Y4 receptor. Journal of neurochemistry 98 9751165
2000 ATP, an agonist at the rat P2Y(4) receptor, is an antagonist at the human P2Y(4) receptor. Molecular pharmacology 90 10779375
2000 P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors are coupled to Rho and Rho kinase activation in vascular myocytes. American journal of physiology. Heart and circulatory physiology 88 10843869
2006 Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors. Journal of medicinal chemistry 85 17125260
1998 Evidence that P2Y4 nucleotide receptors are involved in the regulation of rat aortic smooth muscle cells by UTP and ATP. British journal of pharmacology 81 9690862
1996 Cloned and transfected P2Y4 receptors: characterization of a suramin and PPADS-insensitive response to UTP. British journal of pharmacology 81 8968535
2002 Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors. Journal of medicinal chemistry 76 11754592
2003 Loss of nucleotide regulation of epithelial chloride transport in the jejunum of P2Y4-null mice. Molecular pharmacology 72 12644577
2005 K+ secretion activated by luminal P2Y2 and P2Y4 receptors in mouse colon. The Journal of physiology 65 15718265
2013 P2Y4 receptor-mediated pinocytosis contributes to amyloid beta-induced self-uptake by microglia. Molecular and cellular biology 60 24001770
2004 Expression of P2Y1, P2Y2, P2Y4, and P2Y6 receptor subtypes in the rat retina. Investigative ophthalmology & visual science 60 15452043
2003 Human keratinocytes express multiple P2Y-receptors: evidence for functional P2Y1, P2Y2, and P2Y4 receptors. The Journal of investigative dermatology 58 12603858
2001 Molecular cloning and characterization of the mouse P2Y4 nucleotide receptor. European journal of pharmacology 58 11290369
2005 The role of epithelial P2Y2 and P2Y4 receptors in the regulation of intestinal chloride secretion. British journal of pharmacology 57 16056234
1998 A Study on UV Filter Chemicals from Annex VII of European Union Directive 76/768/EEC, in the In Vitro 3T3 NRU Phototoxicity Test. Alternatives to laboratory animals : ATLA 56 26042493
2002 Immunolocalization of P2Y4 and P2Y2 purinergic receptors in strial marginal cells and vestibular dark cells. The Journal of membrane biology 51 11891569
2003 Tumor necrosis factor alpha-induced apoptosis in astrocytes is prevented by the activation of P2Y6, but not P2Y4 nucleotide receptors. Biochemical pharmacology 49 12623123
2000 Differential regulation of the uridine nucleotide-activated P2Y4 and P2Y6 receptors. SER-333 and SER-334 in the carboxyl terminus are involved in agonist-dependent phosphorylation desensitization and internalization of the P2Y4 receptor. The Journal of biological chemistry 49 11114308
2004 Mechanically evoked reflex electrogenic chloride secretion in rat distal colon is triggered by endogenous nucleotides acting at P2Y1, P2Y2, and P2Y4 receptors. The Journal of comparative neurology 48 14689471
2003 Characterization of P2X3, P2Y1 and P2Y4 receptors in cultured HEK293-hP2X3 cells and their inhibition by ethanol and trichloroethanol. Journal of neurochemistry 48 12694404
2005 Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptors. Biochemical pharmacology 47 16359641
2019 HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways. Journal of neuroinflammation 42 30947729
2011 Structural modifications of UMP, UDP, and UTP leading to subtype-selective agonists for P2Y2, P2Y4, and P2Y6 receptors. Journal of medicinal chemistry 41 21417463
2007 P2Y2- and P2Y4 purinergic receptors are over-expressed in human colon cancer. Autonomic & autacoid pharmacology 41 17391276
2007 Comparative analysis of P2Y4 and P2Y6 receptor architecture in native and transfected neuronal systems. Biochimica et biophysica acta 41 17481575
2006 Region-specific distribution of the P2Y4 receptor in enteric glial cells and interstitial cells of Cajal within the guinea-pig gastrointestinal tract. Autonomic neuroscience : basic & clinical 39 16616701
2003 Coupling of the nucleotide P2Y4 receptor to neuronal ion channels. British journal of pharmacology 39 12540532
2003 Agonist versus antagonist action of ATP at the P2Y4 receptor is determined by the second extracellular loop. The Journal of biological chemistry 39 14670966
2011 Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y(4) receptor. Journal of medicinal chemistry 37 21528910
1997 The proliferation potential protein-related (P2P-R) gene with domains encoding heterogeneous nuclear ribonucleoprotein association and Rb1 binding shows repressed expression during terminal differentiation. Proceedings of the National Academy of Sciences of the United States of America 37 9037032
2005 The metabotropic P2Y4 receptor participates in the commitment to differentiation and cell death of human neuroblastoma SH-SY5Y cells. Neurobiology of disease 36 15649700
2015 Loss of mouse P2Y4 nucleotide receptor protects against myocardial infarction through endothelin-1 downregulation. Journal of immunology (Baltimore, Md. : 1950) 31 25595790
2017 Development of Potent and Selective Antagonists for the UTP-Activated P2Y4 Receptor. Journal of medicinal chemistry 30 28306255
2008 Localization and possible function of P2Y(4) receptors in the rodent retina. Neuroscience 30 18625291
2005 P2Y2 and P2Y4 receptors regulate pancreatic Ca(2+)-activated K+ channels differently. Pflugers Archiv : European journal of physiology 28 16075244
2004 Role of the metabotropic P2Y(4) receptor during hypoglycemia: cross talk with the ionotropic NMDAR1 receptor. Experimental cell research 28 15383322
2012 P2Y(4) nucleotide receptor: a novel actor in post-natal cardiac development. Angiogenesis 25 22437266
2002 P2P-R protein localizes to the nucleolus of interphase cells and the periphery of chromosomes in mitotic cells which show maximum P2P-R immunoreactivity. Journal of cellular physiology 24 12064457
2002 P2P-R protein overexpression restricts mitotic progression at prometaphase and promotes mitotic apoptosis. Journal of cellular physiology 24 12384997
2016 Mouse P2Y4 Nucleotide Receptor Is a Negative Regulator of Cardiac Adipose-Derived Stem Cell Differentiation and Cardiac Fat Formation. Stem cells and development 22 27855539
2009 ATP modulates transcription factors through P2Y2 and P2Y4 receptors via PKC/MAPKs and PKC/Src pathways in MCF-7 cells. Archives of biochemistry and biophysics 22 19900397
2011 In vitro induction of apoptosis, necrosis and genotoxicity by cosmetic preservatives: application of flow cytometry as a complementary analysis by NRU. International journal of cosmetic science 20 22118339
2001 Apical P2Y4 purinergic receptor controls K+ secretion by vestibular dark cell epithelium. American journal of physiology. Cell physiology 20 11401851
2019 P2Y4/TSP-1/TGF-β1/pSmad2/3 pathway contributes to acute generalized seizures induced by kainic acid. Brain research bulletin 19 31005663
2012 Gene deletion of P2Y4 receptor lowers exercise capacity and reduces myocardial hypertrophy with swimming exercise. American journal of physiology. Heart and circulatory physiology 19 22865387
2003 Functional potential of P2P-R: a role in the cell cycle and cell differentiation related to its interactions with proteins that bind to matrix associated regions of DNA? Journal of cellular biochemistry 19 12938151
2003 Stable overexpression of specific segments of the P2P-R protein in human MCF-7 cells promotes camptothecin-induced apoptosis. Journal of cellular physiology 19 14566974
1996 Molecular cloning and characterization of a novel orphan receptor (P2P) expressed in human pancreas that shows high structural homology to the P2U purinoceptor. FEBS letters 19 8617367
1993 Exon skipping in the expression of the gene immediately upstream of N-ras (unr/NRU). Biochimica et biophysica acta 19 8439573
2006 The P2Y₄ receptor forms homo-oligomeric complexes in several CNS and PNS neuronal cells. Purinergic signalling 18 18404459
2005 Apical membrane P2Y4 purinergic receptor controls K+ secretion by strial marginal cell epithelium. Cell communication and signaling : CCS 18 16266433
2014 4-Alkyloxyimino derivatives of uridine-5'-triphosphate: distal modification of potent agonists as a strategy for molecular probes of P2Y2, P2Y4, and P2Y6 receptors. Journal of medicinal chemistry 16 24712832
2011 Regional expression of P2Y(4) receptors in the rat central nervous system. Purinergic signalling 16 21769584
2003 Localization of the P2Y4 receptor in the guinea pig organ of Corti. Journal of the American Academy of Audiology 14 14552422
2007 KCNQ1/KCNE1 K+ channel and P2Y4 receptor are co-expressed from the time of birth in the apical membrane of rat strial marginal cells. Acta oto-laryngologica. Supplementum 13 17882567
2007 Changes in P2Y4 receptor expression in rat cochlear outer sulcus cells during development. Hearing research 12 17433586
2005 P2P-R expression is genetically coregulated with components of the translation machinery and with PUM2, a translational repressor that associates with the P2P-R mRNA. Journal of cellular physiology 12 15617101
2005 Demonstration of P2Y4 purinergic receptors in the HT-29 human colon cancer cell line. Autonomic & autacoid pharmacology 12 16176447
2019 Ligand binding and activation of UTP-activated G protein-coupled P2Y2 and P2Y4 receptors elucidated by mutagenesis, pharmacological and computational studies. Biochimica et biophysica acta. General subjects 11 31812541
2016 Functional and molecular evidence for heteromeric association of P2Y1 receptor with P2Y2 and P2Y4 receptors in mouse granulocytes. BMC pharmacology & toxicology 11 27384918
2010 P2Y4-mediated regulation of Na+ absorption in the Reissner's membrane of the cochlea. The Journal of neuroscience : the official journal of the Society for Neuroscience 11 20220010
2021 Synthesis, characterization and biological evaluation of indomethacin derived thioureas as purinergic (P2Y1, P2Y2, P2Y4, and P2Y6) receptor antagonists. Bioorganic chemistry 9 34601296
2016 P2Y4 Nucleotide Receptor in Neuronal Precursors Induces Glutamatergic Subtype Markers in Their Descendant Neurons. Stem cell reports 9 26972684
2009 Comparative analysis of 1-phenyl-2-propanone (P2P), an amphetamine-type stimulant precursor, using stable isotope ratio mass spectrometry: presented in part as a poster at the 2nd meeting of the Joint European Stable Isotope User Meeting (JESIUM), Giens, France, September 2008. Science & justice : journal of the Forensic Science Society 9 19606587
2003 The benefits of the 3T3 NRU test in the safety assessment of cosmetics: long-term experience from pre-marketing testing in the Czech Republic. Toxicology in vitro : an international journal published in association with BIBRA 9 14599479
2002 P2P-R deficiency modifies nocodazole-induced mitotic arrest and UV-induced apoptosis. Anticancer research 9 12553003
2020 P2Y4, P2Y6 and P2Y11 receptors: From the early days of cloning to their function. Biochemical pharmacology 7 33232731
2010 Systems genetics analyses predict a transcription role for P2P-R: molecular confirmation that P2P-R is a transcriptional co-repressor. BMC systems biology 7 20184719
2008 ATP induces guinea pig gallbladder smooth muscle excitability via the P2Y4 receptor and COX-1 activity. American journal of physiology. Gastrointestinal and liver physiology 6 18436624
2005 Activation of a P2Y4-like purinoceptor triggers an increase in cytosolic [Ca2+] in the red blood cells of the lizard Ameiva ameiva (Squamata, Teiidae). Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 6 15665982
2024 Testosterone Enhances KV Currents and Airway Smooth Muscle Relaxation Induced by ATP and UTP through P2Y4 Receptors and Adenylyl Cyclase Pathway. International journal of molecular sciences 4 38731872
2022 Central role of PD-L1 in cardioprotection resulting from P2Y4 nucleotide receptor loss. Frontiers in immunology 4 36248854
2018 Nucleotide receptor P2RY4 is required for head formation via induction and maintenance of head organizer in Xenopus laevis. Development, growth & differentiation 4 30069871
2012 Apical targeting of the P2Y(4) receptor is directed by hydrophobic and basic residues in the cytoplasmic tail. American journal of physiology. Cell physiology 4 23054062
2007 Rapid assessment of correlated amino acids from pair-to-pair (P2P) substitution matrices. Bioinformatics (Oxford, England) 4 17496318
2022 Knockdown of P2Y4 ameliorates sepsis-induced acute kidney injury in mice via inhibiting the activation of the NF-κB/MMP8 axis. Frontiers in physiology 3 36105291
2015 Expression of purinergic receptor P2Y4 in Schwann cell following nerve regeneration. International journal of clinical and experimental medicine 3 26550244
2013 Protein kinase C-mediated ATP stimulation of Na(+)-ATPase activity in LLC-PK1 cells involves a P2Y2 and/or P2Y4 receptor. Archives of biochemistry and biophysics 3 23567840
2006 Reactive blue 2, an antagonist of rat P2Y4, increases K+ secretion in rat cochlea strial marginal cells. Hearing research 3 16839719
2004 Aalpha,beta-methylene ATP enhances P2Y4 contraction of rabbit basilar artery. American journal of physiology. Heart and circulatory physiology 3 15020308
2004 An in vitro phototoxicity assay battery (photohaemolysis and 3T3 NRU PT test) to assess phototoxic potential of fragrances. Alternatives to laboratory animals : ATLA 3 23581161
2022 Loss-of-function N178T variant of the human P2Y4 receptor is associated with decreased severity of coronary artery disease and improved glucose homeostasis. Frontiers in pharmacology 2 36532779
2025 Identification of an anti-inflammatory action of exosome release in P2Y4 loss-mediated cardioprotection. Frontiers in pharmacology 0 41164751
2022 Corrigendum: Central role of PD-L1 in cardioprotection resulting from P2Y4 nucleotide receptor loss. Frontiers in immunology 0 36389796
2022 IN VIVO ACTIVATION OF P2Y4 PURINERGIC RECEPTORS USING ATP IN RAT EPIDERMAL TISSUE. Wiadomosci lekarskie (Warsaw, Poland : 1960) 0 36591760
2012 P2P proteomics -- data sharing for enhanced protein identification. Automated experimentation 0 22293032
2002 [Sal I, Nru I and Mse I restriction fragment length polymorphisms of factor IX gene in Chinese Han people]. Zhongguo shi yan xue ye xue za zhi 0 12513796

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