Affinage

P2RY1

P2Y purinoceptor 1 · UniProt P47900

Length
373 aa
Mass
42.1 kDa
Annotated
2026-04-29
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RY1 encodes a Gq-coupled purinergic receptor activated by extracellular ADP and uridine adenosine tetraphosphate (Up4A) that signals through phospholipase C to mobilize intracellular Ca2+ and engage downstream effectors including PKC, RhoA/Rho kinase, Rac GTPase, p38 MAPK, and H2O2-dependent pathways (PMID:9442040, PMID:14742685, PMID:10843869, PMID:24550450, PMID:25341729). Crystal structures reveal two pharmacologically distinct antagonist-binding sites—an orthosteric pocket within the transmembrane bundle and an allosteric site at the receptor–lipid bilayer interface—while receptor desensitization is controlled by PKC phosphorylation of proximal C-terminal residues and internalization requires GRK-independent phosphorylation of Ser352/Thr358 with β-arrestin-2 recruitment, followed by ALIX/YPX3L motif–dependent lysosomal sorting (PMID:25822790, PMID:15665114, PMID:19741005, PMID:27301021). Physiologically, P2RY1 is essential for ADP-induced platelet shape change and aggregation, mediates fast inhibitory purinergic neurotransmission throughout the gastrointestinal tract, regulates astrocyte Ca2+ dynamics and phenotype switching in the brain, modulates thermal nociception in sensory neurons, and controls M-current–dependent neuronal excitability in hippocampal neurons (PMID:9639511, PMID:22371476, PMID:25406732, PMID:28494865, PMID:21310055, PMID:16957090).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Identifying that the cloned human P2Y1 receptor couples to phospholipase C/inositol phosphate signaling upon ADP stimulation, and that adenosine bisphosphate derivatives serve as selective competitive antagonists, established the receptor's pharmacological identity and Gq-PLC coupling.

    Evidence Heterologous expression in 1321N1 astrocytoma cells with inositol phosphate accumulation and Schild analysis

    PMID:8913364

    Open questions at the time
    • Endogenous cellular functions not yet demonstrated
    • G protein specificity not directly tested
  2. 1998 High

    Demonstrating that P2Y1 mediates ADP-induced Ca2+ mobilization, platelet shape change, and aggregation—while having no role in adenylyl cyclase inhibition—resolved the long-standing question of which receptor subtype drives the initial phase of platelet activation and separated P2Y1 from the P2TAC/P2Y12 pathway.

    Evidence Selective P2Y1 antagonists in human platelets, endothelial cells, and P2Y1-transfected Jurkat cells; platelet cDNA cloning

    PMID:9442040 PMID:9639511

    Open questions at the time
    • Knockout validation not yet available
    • Signaling intermediates between Gq and cytoskeletal reorganization uncharacterized
  3. 2000 Medium

    Establishing that P2Y1 couples to RhoA/Rho kinase–dependent actin remodeling and to p38 MAPK activation in platelets and vascular myocytes expanded the downstream signaling repertoire beyond PLC/Ca2+ to include cytoskeletal and stress kinase pathways.

    Evidence Transfection of individual P2Y receptors in Swiss 3T3 cells; RhoA membrane translocation; dominant-negative RhoA; Rho kinase inhibitor pharmacology; p38 MAPK activity in human platelets

    PMID:10759852 PMID:10843869

    Open questions at the time
    • Direct biochemical link between Gαq and RhoA activation not delineated
    • p38 activation mechanism (aspirin-sensitive factor) not molecularly identified
  4. 2001 Medium

    Showing that P2Y1 antagonism blocks ADP-induced translocation of Cdc42, Rac1, and RhoA to the platelet cytoskeleton along with filopodia formation linked the receptor to the full Rho-family GTPase cascade governing platelet shape change.

    Evidence Electron microscopy and biochemical cytoskeletal fractionation with selective P2Y1 antagonist in human platelets

    PMID:11341507

    Open questions at the time
    • Integrin dependence versus independence of each GTPase step unclear
    • No genetic loss-of-function confirmation
  5. 2003 High

    Platelet-lineage-specific P2Y1 transgenic overexpression causing hyper-reactivity, enhanced aggregation, granule secretion, shortened bleeding time, and increased thromboembolism provided the first genetic gain-of-function proof that P2Y1 receptor density directly controls thrombotic risk in vivo.

    Evidence Megakaryocyte/platelet-specific transgenic mice; saturation binding; aggregometry; in vivo thromboembolism model

    PMID:12871553

    Open questions at the time
    • Corresponding loss-of-function platelet phenotype not shown in this study
    • Whether increased receptor density shifts agonist preference unexamined
  6. 2004 High

    Reconstituting purified P2Y1R with Gαq/β1γ2 in proteoliposomes and measuring agonist-stimulated GTP hydrolysis provided direct biochemical proof of Gq coupling, established the intrinsic agonist rank order (2MeSADP > ADP >> ATP), and showed RGS4 and PLCβ1 function as GAPs for Gαq in this system.

    Evidence Purified receptor reconstitution in proteoliposomes; radioligand binding; steady-state GTPase assay

    PMID:14742685

    Open questions at the time
    • Structural basis of agonist selectivity not resolved
    • Other potential G protein couplings not tested in reconstituted system
  7. 2005 High

    Dissecting P2Y1 desensitization as PKC-dependent (not GRK-dependent) using dominant-negative GRKs and siRNA, in contrast to GRK-dependent P2Y12 desensitization, established that the two platelet ADP receptors use fundamentally different regulatory mechanisms.

    Evidence Dominant-negative GRK2/GRK6 overexpression; GRK siRNA knockdown; PKC inhibitors in platelets and 1321N1 cells

    PMID:15665114

    Open questions at the time
    • Specific PKC isoform responsible not identified
    • Phosphorylation sites mediating PKC desensitization not mapped
  8. 2005 Medium

    Demonstrating that P2Y1 activates Rac GTPase and PAK through Gq while P2Y12 potentiates this via Gi/Gβγ resolved how two ADP receptors cooperate to achieve full small GTPase activation during platelet signaling.

    Evidence Selective P2Y1/P2Y12 antagonists; Rac-GTP pull-down; Gβγ scavenger peptide in human platelets

    PMID:16194206

    Open questions at the time
    • Intermediate between Gαq and Rac guanine nucleotide exchange factor not identified
    • Relative contributions to platelet spreading versus aggregation unclear
  9. 2006 High

    Finding that P2Y1 activation in astrocytes triggers Ca2+-dependent glutamate exocytosis requiring TNFα and prostaglandin E2 as co-factors, and that P2Y1 inhibits M-type K+ current in hippocampal neurons to increase excitability, established two distinct neuronal circuit–level roles for P2Y1 signaling in the brain.

    Evidence TIRFM vesicle imaging and Ca2+ imaging in astrocytes from TNFα−/− and TNFR1−/− mice; whole-cell patch-clamp with MRS2179 in hippocampal neurons

    PMID:16882655 PMID:16957090

    Open questions at the time
    • Identity of the gliotransmitter release machinery downstream of Ca2+ not fully defined
    • Whether M-current modulation occurs in vivo not shown
  10. 2009 High

    Mapping P2Y1 internalization to distal C-terminal phosphorylation sites Ser352/Thr358 and β-arrestin-2 recruitment—distinct from the proximal PKC sites controlling desensitization—demonstrated that functional uncoupling and endocytic removal are mechanistically separable regulatory events.

    Evidence Site-directed mutagenesis; confocal microscopy of fluorescent-tagged receptor; ELISA-based surface quantification

    PMID:19741005

    Open questions at the time
    • The kinase phosphorylating Ser352/Thr358 not identified (shown to be GRK-independent)
    • β-arrestin-2 binding determinants on receptor not mapped
  11. 2010 Medium

    Identifying SNX1 as a retromer-independent regulator of P2Y1 slow recycling revealed a non-canonical post-endocytic trafficking pathway for this receptor.

    Evidence SNX1 dominant-negative inhibition; siRNA knockdown of retromer components; confocal receptor tracking

    PMID:20070609

    Open questions at the time
    • Mechanism by which SNX1 retards recycling not defined
    • Not validated in endogenous P2Y1-expressing primary cells
  12. 2012 High

    Complete loss of fast inhibitory junction potentials in P2ry1−/− mouse colon, and extension to antrum and cecum, established P2Y1 as the obligate post-junctional receptor for purinergic inhibitory neuromuscular transmission throughout the gastrointestinal tract, with β-NAD and ADP-ribose (not ATP) as likely endogenous transmitters.

    Evidence P2ry1−/− knockout mice; microelectrode recordings; pharmacological dissection; video imaging of colonic transit

    PMID:22371476 PMID:23323764

    Open questions at the time
    • Endogenous purinergic neurotransmitter identity debated (β-NAD vs. ADP-ribose)
    • Mechanism of SK channel coupling downstream of P2Y1 in smooth muscle not fully resolved
  13. 2014 High

    Multiple 2014 studies expanded the physiological scope: Up4A was identified as a potent endogenous P2Y1 agonist for enteric inhibitory neurotransmission; P2Y1-RhoA signaling in platelets was shown to drive leukocyte recruitment in allergic inflammation; P2Y1-mediated H2O2 production was established as a second messenger activating AMPK, Rac1, and Flt3 transactivation in endothelial cells; and P2Y1 blockade normalized astrocytic hyperactivity in an Alzheimer's disease mouse model.

    Evidence P2ry1−/− mice with electrophysiology and HPLC; platelet reconstitution in thrombocytopenic mice; FRET-based H2O2/Rac1 biosensors in endothelial cells; in vivo multiphoton Ca2+ imaging in AD model

    PMID:24550450 PMID:25341729 PMID:25406732 PMID:25445826

    Open questions at the time
    • Source of Up4A in enteric nervous system not identified
    • Whether H2O2-dependent signaling occurs in platelets or only endothelium unknown
    • Causal relationship between P2Y1 and Alzheimer's pathogenesis not established
  14. 2015 High

    Crystal structures of P2Y1R bound to a nucleotide antagonist (orthosteric) and a non-nucleotide antagonist (allosteric, at the lipid-bilayer interface) revealed two pharmacologically distinct binding sites, providing the first atomic-resolution framework for structure-based drug design targeting this receptor class.

    Evidence X-ray crystallography at 2.7 Å and 2.2 Å resolution

    PMID:25822790

    Open questions at the time
    • No agonist-bound or active-state structure available
    • Structural basis for Gq selectivity not resolved
  15. 2016 High

    Identifying the ALIX-binding YPX3L motif in the second intracellular loop as required for ubiquitin-independent lysosomal sorting completed the post-endocytic trafficking itinerary from internalization through degradation.

    Evidence ALIX knockdown; YPX3L motif mutagenesis; GFP-tagged receptor fluorescence microscopy

    PMID:27301021

    Open questions at the time
    • Whether lysosomal sorting is the dominant degradation route in primary cells not confirmed
    • Interaction between SNX1-recycling and ALIX-degradation pathways not examined
  16. 2017 High

    Demonstrating that microglial cytokines downregulate astrocytic P2Y1 to promote scar formation after brain injury, with P2Y1 overexpression counteracting and knockdown facilitating scarring, established P2Y1 as a central switch governing astrocyte phenotype in neuroinflammation.

    Evidence Astrocyte-specific P2Y1 overexpression and knockdown mouse models; in vitro injury assays; cytokine blocking

    PMID:28494865

    Open questions at the time
    • Downstream transcriptional program controlled by P2Y1 in reactive astrocytes not mapped
    • Whether this mechanism operates in chronic neurodegenerative disease unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • No agonist-bound active-state structure of P2Y1R exists, the kinase phosphorylating the distal C-terminal internalization sites remains unidentified, the precise endogenous purinergic neurotransmitter at enteric P2Y1 receptors is debated, and the structural basis for Gq selectivity over other G proteins has not been determined.
  • Active-state crystal or cryo-EM structure needed
  • Identity of kinase for Ser352/Thr358 phosphorylation unknown
  • Endogenous enteric neurotransmitter (β-NAD, ADP-ribose, or Up4A) not definitively established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 5 R-HSA-112316 Neuronal System 4 R-HSA-168256 Immune System 1
Partners
ALIXARRB2GNA11GNAQPLCB1RAC1RHOASNX1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Crystal structures of human P2Y1R revealed two distinct ligand-binding sites: nucleotide antagonist MRS2500 binds within the seven-transmembrane bundle (orthosteric site), while non-nucleotide antagonist BPTU binds an allosteric pocket on the external receptor interface with the lipid bilayer, outside the helical bundle. X-ray crystallography at 2.7 Å (MRS2500 complex) and 2.2 Å (BPTU complex) resolution Nature High 25822790
1998 P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and platelet shape change; selective P2Y1 antagonists (A3P5PS, A3P5P, A2P5P) blocked Ca2+ increases and shape change but not ADP-induced inhibition of adenylyl cyclase, demonstrating that P2Y1 is coupled to phospholipase C/Ca2+ signaling and is distinct from the P2TAC receptor. Pharmacological antagonism with selective antagonists in human platelets; cloning from human platelet cDNA library The Journal of biological chemistry High 9442040 9639511
1998 The P2Y1 receptor is necessary to trigger ADP-induced platelet aggregation; P2Y1 selective antagonists blocked Ca2+ mobilization, shape change, and aggregation in platelets, endothelial cells, and P2Y1-transfected Jurkat cells, while having no effect on ADP-induced inhibition of adenylyl cyclase. Pharmacological antagonism in human platelets, rat brain capillary endothelial cells, and P2Y1-transfected Jurkat cells; receptor cloning and heterologous expression Blood High 9442040 9639511
2004 Purified human P2Y1 receptor, reconstituted in proteoliposomes with heterotrimeric Gαq β1γ2, stimulates steady-state GTP hydrolysis (Gq activation) upon agonist addition; agonist affinities determined directly show 2MeSADP > ADP >> ATP, and RGS4 and PLCβ1 act as GTPase-activating proteins for Gαq/Gα11 in P2Y1R-containing vesicles. Reconstitution in proteoliposomes with purified receptor and G proteins; radioligand binding with [3H]MRS2279; steady-state GTP hydrolysis assay Molecular pharmacology High 14742685
2016 Molecular dynamics simulations showed that BPTU antagonizes P2Y1R by stabilizing extracellular helix bundles and increasing lipid order, while MRS2500 blocks the ligand-binding site; ADP binding breaks an ionic lock within the receptor and forms a continuous water channel leading to receptor activation. All-atom molecular dynamics simulations (20 μs total) based on crystal structures Angewandte Chemie (International ed. in English) Medium 27460867
2005 P2Y1 desensitization in platelets and 1321N1 cells is mediated by protein kinase C (PKC), not by GRK2 or GRK6, whereas P2Y12 desensitization is GRK-dependent; dominant-negative GRK mutants and siRNA knockdown demonstrated that GRKs phosphorylate P2Y12 but not P2Y1. Dominant-negative kinase mutant overexpression; siRNA knockdown of GRK2/GRK6; pharmacological PKC inhibition in human platelets and 1321N1 cells Blood High 15665114
2009 P2Y1 receptor internalization and β-arrestin-2 recruitment require phosphorylation of distal C-terminal residues Ser352 and Thr358, while PKC-mediated desensitization depends on proximal C-terminal phosphorylation sites; thus receptor desensitization and internalization are mediated by distinct phosphorylation sites and kinases. Site-directed mutagenesis of phosphorylation sites; confocal microscopy of fluorescent protein-tagged receptors; ELISA-based cell-surface receptor quantification Molecular pharmacology High 19741005
2016 After agonist-induced activation, P2Y1 sorts to lysosomes for degradation independent of direct receptor ubiquitination; this sorting is mediated by a YPX3L motif in the second intracellular loop that recruits the adaptor protein ALIX. Depletion of ALIX or mutation of the YPX3L motif inhibits P2Y1 sorting into multivesicular endosomes/lysosomes. ALIX knockdown; site-directed mutagenesis of YPX3L motif; fluorescence microscopy of GFP-tagged receptor PloS one High 27301021
2010 P2Y1 receptor recycling after agonist-induced endocytosis occurs via a slow recycling pathway regulated by Sorting Nexin 1 (SNX1); SNX1 inhibition dramatically increases the rate of P2Y1 recycling, while inhibition of retromer components Vps26/Vps35 has no effect, demonstrating retromer-independent SNX1 regulation. SNX1 dominant-negative inhibition; siRNA knockdown of retromer components; confocal microscopy tracking of receptor trafficking Traffic (Copenhagen, Denmark) Medium 20070609
2001 P2Y1 receptor mediates ADP-induced platelet shape change through Rho GTPase pathway: P2Y1 antagonism blocked cytoskeletal translocation of cdc42, rac1, and rhoA, actin polymerization, filopodia formation, and centralization of secretory granules in an integrin αIIbβ3-dependent manner. Selective P2Y1 antagonist (A2P5P) in electron microscopy and biochemical assays of platelet cytoskeletal protein translocation Thrombosis and haemostasis Medium 11341507
2005 ADP activates Rac GTPase and its effector PAK in platelets via the P2Y1 receptor through a Gq-dependent pathway; P2Y12 receptor alone cannot activate Rac, but secreted ADP potentiates Rac activation by other agonists via P2Y12/Gi; Gβγ subunit scavenger peptide blocked P2Y12-dependent co-activation. Selective P2Y1/P2Y12 antagonists; Rac activation pull-down assay (PAK-GST); pharmacological inhibition of Gq, Gi, PI3K; Gβγ peptide inhibitor in human platelets Journal of thrombosis and haemostasis : JTH Medium 16194206
2000 P2Y1 receptor couples to Rho/Rho kinase signaling in vascular myocytes: P2Y1 stimulation increases membrane-bound RhoA, promotes actin stress fiber formation inhibited by C3 exoenzyme and Y-27632 (Rho kinase inhibitor), and causes Ca2+ sensitization in aortic rings; transfection confirmed that P2Y1 subtype directly drives Rho kinase-dependent actin reorganization. Transfection of Swiss 3T3 cells with individual P2Y receptors; RhoA membrane translocation assay; C3 exoenzyme and Y-27632 pharmacology; dominant-negative RhoA expression American journal of physiology. Heart and circulatory physiology Medium 10843869
2005 Metabotropic P2Y1 receptors in rat dorsal root ganglion neurons inhibit ionotropic P2X3 receptor-mediated currents; this cross-inhibition is blocked by the G protein inhibitor GDP-β-S and the P2Y1 antagonist MRS2179, but not by pertussis toxin, indicating Gαq/11 (not Gi/o) G protein mediation. Whole-cell patch-clamp recordings; selective pharmacological inhibitors; G protein inhibitors in cultured rat DRG neurons European journal of pharmacology Medium 16181623
2006 P2Y1 receptor activation in astrocytes triggers regulated glutamate exocytosis via Ca2+ release from internal stores; this process requires TNFα and prostaglandin E2 as co-factors, as blocking either abolishes P2Y1-evoked glutamate release. Astrocytes from TNFα-/- or TNFR1-/- mice show deficient glutamate release and altered Ca2+ signaling. Total internal fluorescence reflection imaging of labeled vesicles; Ca2+ imaging; knockout mouse astrocytes; pharmacological inhibitors; hippocampal slice recordings The Journal of biological chemistry High 16882655
2012 P2Y1 receptor is the post-junctional receptor mediating fast inhibitory junction potentials (fIJP) in mouse colon; P2ry1-/- mice completely lack fIJPs and purinergic contractile responses; β-NAD and ADP-ribose responses were abolished in P2ry1-/- mice, while ATP and ADP responses were retained, identifying the receptor specificity for enteric purinergic neurotransmission. Genetic knockout mice (P2ry1-/-); microelectrode recordings; pharmacological dissection; video imaging of colonic transit The Journal of physiology High 22371476
2013 P2Y1 receptor is the general mechanism of purinergic inhibition throughout the GI tract (antrum and cecum), as confirmed in P2Y1-/- mice which lack purinergic IJPs while preserving nitrergic neurotransmission. Genetic knockout mice (P2Y1-/-); microelectrode recordings; pharmacological validation with MRS2365 and MRS2500 Neurogastroenterology and motility High 23323764
2006 P2Y1 receptor activation in hippocampal pyramidal neurons inhibits M-type K+ current (IM) and increases neuronal firing; this is blocked by the selective P2Y1 antagonist MRS2179 and by the M-channel blocker XE991, establishing P2Y1-mediated M-current inhibition as the mechanism underlying nucleotide-induced neuronal excitability. Whole-cell patch-clamp; selective P2Y1 antagonist MRS2179; immunostaining for P2Y1 in cultured rat hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 16957090
2014 Astrocytic hyperactivity in an Alzheimer's disease mouse model is completely normalized by P2Y1 receptor inhibition; astroglial Ca2+ transients and waves are mediated by P2 purinoreceptors, with P2Y1R blockade (but not P2X receptor blockade) normalizing activity; nucleotide release through connexin hemichannels and increasing cortical ADP augments this hyperactivity. In vivo multiphoton Ca2+ imaging; selective P2Y1R antagonists; P2X vs P2Y pharmacological dissection in AD mouse model Nature communications High 25406732
2017 Microglia transform astrocytes into a neuroprotective phenotype after traumatic brain injury by secreting cytokines that downregulate P2Y1 receptor expression in astrocytes; astrocyte-specific P2Y1 overexpression counteracted scar formation while P2Y1 knockdown facilitated it, demonstrating P2Y1 as a key regulator of astrocyte phenotype switching. Astrocyte-specific P2Y1 overexpression and knockdown mouse models; in vitro injury assays; immunostaining; cytokine blocking Cell reports High 28494865
2014 RhoA signaling downstream of platelet P2Y1 receptor (not P2Y12) mediates platelet-dependent leukocyte recruitment during allergic inflammation; P2Y1 activation in platelets induces RhoA activity in vivo, and Rho kinase 1 inhibition in platelets abolished leukocyte chemotaxis, demonstrating a P2Y1-RhoA axis distinct from the P2Y12-hemostasis pathway. Selective receptor antagonists in vivo; thrombocytopenic mice reconstituted with pharmacologically pretreated platelets; flow cytometry; RhoA activity assay The Journal of allergy and clinical immunology Medium 25445826
2000 P2Y1 receptor mediates ADP-induced generation of a p38 MAP kinase-activating factor in human platelets via an aspirin-sensitive pathway; selective P2Y1 antagonist A2P5P inhibited this response while P2TAC and P2X1 antagonists had no effect. Selective pharmacological antagonists; p38 MAP kinase activation assay in human platelets European journal of biochemistry Medium 10759852
2015 Electrical stimulation of skeletal muscle triggers ROS production via a P2Y1-PKC-NOX2 pathway; extracellular ATP released from muscle activates P2Y1 receptors (MRS2365 mimics effect; P2Y1 antagonist MRS2179 blocks it), leading to PKC-dependent NOX2 activation and H2O2 production. Selective P2Y1 agonist and antagonist; fluorescent ROS probes; NOX2 and PKC inhibitors in skeletal muscle fibers and isolated muscle fibres PloS one Medium 26053483
2014 ADP activation of P2Y1 receptor in endothelial cells produces H2O2-dependent phosphorylation of eNOS, AMPK, MARCKS, and c-Abl; H2O2 mediates downstream Rac1-dependent AMPK and CrkII signaling; P2Y1 activation also transactivates the receptor tyrosine kinase Flt3. ADP-stimulated H2O2 increases were localized to cytosol and caveolae. PEG-catalase H2O2 scavenger; FRET-based Rac1 and H2O2 biosensors (HyPer2) with subcellular targeting; receptor tyrosine kinase screen; pharmacological inhibitors in endothelial cells Proceedings of the National Academy of Sciences of the United States of America Medium 24550450
2008 Membrane depolarization directly potentiates P2Y1 receptor-evoked IP3-dependent Ca2+ mobilization in megakaryocytes, revealing voltage-dependence of this Gq-coupled GPCR; depolarization can also stimulate Ca2+ release in the presence of competitive antagonists, indicating a novel coincidence detection mechanism. Simultaneous whole-cell patch-clamp and fura-2 fluorescence in rat megakaryocytes; voltage protocols with multiple agonists and antagonists British journal of pharmacology Medium 18414379
1996 The cloned human P2Y1 receptor, when stably expressed in 1321N1 astrocytoma cells, activates phospholipase C/inositol phosphate signaling in response to ADP and 2-methylthioATP; adenosine bisphosphate derivatives (A3P5PS, A3P5P, A2P5P) act as competitive antagonists of this receptor without affecting P2Y2, P2Y4, or P2Y6 receptors. Heterologous expression; inositol phosphate accumulation assay; Schild analysis of competitive antagonism Molecular pharmacology High 8913364
2004 NTPDase1 (hydrolyzes both NTPs and NDPs) reduces P2Y1 receptor signaling by degrading agonist ADP, while NTPDase2 (preferentially hydrolyzes NTPs) converts ATP to ADP, thereby increasing basal P2Y1 receptor activity; co-expression or co-culture of these ectonucleotidases differentially modulates the EC50 for P2Y1 receptor agonists. Co-expression and co-culture of P2Y1R with NTPDase1 or NTPDase2 in cell lines; inositol phosphate accumulation assay Molecular pharmacology Medium 15496502
2003 P2Y1 receptor and NTPDase1/CD39 are co-localized within caveolae of human placental endothelial cells, suggesting that the ectonucleotidase directly controls local nucleotide concentration and P2Y1 receptor activation at these membrane microdomains. Immunohistochemistry and immunogold electron microscopy of human placental tissue European journal of histochemistry : EJH Low 15590415
2011 P2Y1 receptor activation induces apoptosis and inhibits proliferation of PC-3 prostate cancer cells through the MAP kinase pathway; selective P2Y1 agonist MRS2365 activated caspase-3 and increased LDH release, effects blocked by P2Y1 antagonist MRS2500, P2Y1 siRNA, and the MAP kinase inhibitor PD98059. Selective agonist/antagonist; siRNA knockdown; caspase-3 assay; LDH release; annexin-V staining; MTT proliferation assay in PC-3 cells Biochemical pharmacology Medium 21632028
2003 Transgenic mice overexpressing P2Y1 receptor specifically in megakaryocytes/platelets (84% increase in receptor density) display platelet hyper-reactivity: enhanced aggregation to ADP and low-dose collagen, ADP-induced granule secretion (not seen in wild-type), shortened bleeding time, and increased sensitivity to in vivo thromboembolism. Platelet-lineage-specific transgenic overexpression; saturation binding assay; aggregometry; in vivo thromboembolism model Journal of thrombosis and haemostasis : JTH High 12871553
2011 P2Y1 receptor is required for normal thermal sensitivity in cutaneous polymodal nociceptors (CPMs); P2Y1-/- mice show increased mean heat threshold and decreased peak firing during thermal ramps, and altered cold threshold, without changes in mechanical sensitivity. Genetic knockout mice (P2Y1-/-); ex vivo electrophysiological recordings from skin-nerve-DRG preparation with calibrated thermal stimuli Molecular pain Medium 21310055
2014 Uridine adenosine tetraphosphate (Up4A) is a potent native agonist for P2Y1R and small-conductance K+ (SK) channel activation in human and mouse colon; Up4A-induced relaxation and hyperpolarization were blocked by the P2Y1R antagonist MRS2500 and were absent in P2ry1-/- mice, and Up4A responses are not mediated by its metabolites. Selective P2Y1R antagonist MRS2500; P2ry1-/- genetic knockout mice; electrophysiology; Ca2+ imaging in P2Y1R-expressing astrocytoma cells; HPLC for metabolite analysis Proceedings of the National Academy of Sciences of the United States of America High 25341729
2009 ATP released from skeletal muscle during electrical stimulation inhibits chloride channels via P2Y1 receptors: the P2Y1-selective agonist 2MeSADP (EC50 ~160 nM) increased input resistance and prolonged mEPP falling phase; these effects were blocked by the P2Y1 antagonist MRS2179 and anthracene-9-carboxylic acid (Cl- channel blocker). Intracellular microelectrode recordings in innervated rat muscle; selective P2Y1 agonist and antagonist; chloride channel pharmacology The Journal of physiology Medium 19805741
2003 P2Y12 receptor (not P2Y1) is involved in thrombin-induced phosphatidylserine exposure on platelets and subsequent thrombin generation in platelet-rich plasma; P2Y1 is not involved in procoagulant activity, but both receptors contribute to platelet-leukocyte interactions mediated by P-selectin exposure. Selective P2Y1 (MRS2179) and P2Y12 (AR-C69931MX) antagonists; flow cytometry for PS exposure; thrombin generation assay; P-selectin assay in human platelets Arteriosclerosis, thrombosis, and vascular biology Medium 12933533

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. The Journal of biological chemistry 377 9442040
2015 Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 287 25822790
2017 Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation. Cell reports 274 28494865
2014 Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nature communications 260 25406732
1996 Identification of competitive antagonists of the P2Y1 receptor. Molecular pharmacology 225 8913364
1998 The P2Y1 receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation. Blood 206 9639511
2006 P2Y1 receptor-evoked glutamate exocytosis from astrocytes: control by tumor necrosis factor-alpha and prostaglandins. The Journal of biological chemistry 176 16882655
2017 LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals. Cell death and differentiation 136 28644440
2005 P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood 132 15665114
2006 Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Thrombosis research 123 16581111
1998 ATP derivatives are antagonists of the P2Y1 receptor: similarities to the platelet ADP receptor. Molecular pharmacology 117 9547364
2003 Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochemistry and cell biology 115 14564529
1996 Cloning and chromosomal localization of the human P2Y1 purinoceptor. Biochemical and biophysical research communications 115 8579591
1998 Deoxyadenosine bisphosphate derivatives as potent antagonists at P2Y1 receptors. Journal of medicinal chemistry 111 9457242
2003 Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arteriosclerosis, thrombosis, and vascular biology 108 12933533
2003 Reduced expression of P2Y1 receptors in connexin43-null mice alters calcium signaling and migration of neural progenitor cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 106 14673009
2012 P2Y1 purinoreceptors are fundamental to inhibitory motor control of murine colonic excitability and transit. The Journal of physiology 104 22371476
2004 Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arteriosclerosis, thrombosis, and vascular biology 100 15514209
2004 Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptor. Molecular pharmacology 98 14742685
2001 Effects of P2Y(1) and P2Y(12) receptor antagonists on platelet aggregation induced by different agonists in human whole blood. Platelets 96 11674863
2018 P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model. The Journal of experimental medicine 92 29724785
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
2003 P2X4, P2Y1 and P2Y2 receptors on rat alveolar macrophages. British journal of pharmacology 82 12970084
1996 Cloning and tissue distribution of the human P2Y1 receptor. Biochemical and biophysical research communications 82 8630005
2004 Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog. The Journal of pharmacology and experimental therapeutics 78 15345752
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
2015 ROS Production via P2Y1-PKC-NOX2 Is Triggered by Extracellular ATP after Electrical Stimulation of Skeletal Muscle Cells. PloS one 71 26053483
2016 Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia. Oncogene 65 26973243
2008 A molecular signaling model of platelet phosphoinositide and calcium regulation during homeostasis and P2Y1 activation. Blood 64 18596227
2014 RhoA signaling through platelet P2Y₁ receptor controls leukocyte recruitment in allergic mice. The Journal of allergy and clinical immunology 60 25445826
2009 Low-intensity pulsed ultrasound-dependent osteoblast proliferation occurs by via activation of the P2Y receptor: role of the P2Y1 receptor. Bone 60 19781676
2009 P2Y(1) receptors mediate inhibitory neuromuscular transmission in the rat colon. British journal of pharmacology 59 19906120
2000 Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochimica et biophysica acta 58 11004484
2009 Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets 56 19637098
2007 Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin. Pharmacogenomics 56 17559347
2005 P2Y1 and cysteinyl leukotriene receptors mediate purine and cysteinyl leukotriene co-release in primary cultures of rat microglia. International journal of immunopathology and pharmacology 56 15888248
1999 Structure-activity relationships of bisphosphate nucleotide derivatives as P2Y1 receptor antagonists and partial agonists. Journal of medicinal chemistry 56 10229631
2008 New evidence for purinergic signaling in the olfactory bulb: A2A and P2Y1 receptors mediate intracellular calcium release in astrocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 54 18310463
2010 P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells. American journal of physiology. Cell physiology 51 20962269
2000 Immunohistochemical localization of the P2Y1 purinergic receptor in Alzheimer's disease. Neuroreport 51 11117494
1998 ATP-induced arachidonic acid release in cultured astrocytes is mediated by Gi protein coupled P2Y1 and P2Y2 receptors. Glia 51 9517568
2016 ALIX Regulates the Ubiquitin-Independent Lysosomal Sorting of the P2Y1 Purinergic Receptor via a YPX3L Motif. PloS one 49 27301021
2018 P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics. Cell reports 48 29490276
2008 Mechanical stress induces osteopontin via ATP/P2Y1 in periodontal cells. Journal of dental research 48 18502966
2001 Two subtypes of G protein-coupled nucleotide receptors, P2Y(1) and P2Y(2) are involved in calcium signalling in glioma C6 cells. British journal of pharmacology 48 11159687
2005 Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons. European journal of pharmacology 47 16181623
2003 The P2Y(1) receptor as a target for new antithrombotic drugs: a review of the P2Y(1) antagonist MRS-2179. Cardiovascular drug reviews 47 12595918
2016 The Molecular Mechanism of P2Y1 Receptor Activation. Angewandte Chemie (International ed. in English) 46 27460867
2010 Regulation of P2Y1 receptor traffic by sorting Nexin 1 is retromer independent. Traffic (Copenhagen, Denmark) 46 20070609
2003 Lineage-specific overexpression of the P2Y1 receptor induces platelet hyper-reactivity in transgenic mice. Journal of thrombosis and haemostasis : JTH 45 12871553
2001 Differential involvement of the P2Y1 and P2YT receptors in the morphological changes of platelet aggregation. Thrombosis and haemostasis 45 11341507
2007 Co-localization and functional cross-talk between A1 and P2Y1 purine receptors in rat hippocampus. The European journal of neuroscience 42 17672857
2000 The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets. European journal of biochemistry 41 10759852
2014 Participation of peripheral P2Y1, P2Y6 and P2Y11 receptors in formalin-induced inflammatory pain in rats. Pharmacology, biochemistry, and behavior 40 25449358
2011 Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation. Pain 40 22137295
2006 Regulation of death and survival in astrocytes by ADP activating P2Y1 and P2Y12 receptors. Biochemical pharmacology 40 16934758
2005 A differential role of the platelet ADP receptors P2Y1 and P2Y12 in Rac activation. Journal of thrombosis and haemostasis : JTH 40 16194206
2011 Activation of the P2Y1 receptor induces apoptosis and inhibits proliferation of prostate cancer cells. Biochemical pharmacology 39 21632028
2010 The ecto-nucleotidase NTPDase1 differentially regulates P2Y1 and P2Y2 receptor-dependent vasorelaxation. British journal of pharmacology 39 20067476
2006 Activation of P2Y1 nucleotide receptors induces inhibition of the M-type K+ current in rat hippocampal pyramidal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 16957090
2019 Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 31048325
2018 Role of Purinergic Receptor P2Y1 in Spatiotemporal Ca2+ Dynamics in Astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 29305530
1997 An examination of deoxyadenosine 5'(alpha-thio)triphosphate as a ligand to define P2Y receptors and its selectivity as a low potency partial agonist of the P2Y1 receptor. British journal of pharmacology 36 9154346
2013 P2Y(1) knockout mice lack purinergic neuromuscular transmission in the antrum and cecum. Neurogastroenterology and motility 35 23323764
2001 P2y1 and P2y2 receptor-operated Ca2+ signals in primary cultures of cardiac microvascular endothelial cells. Microvascular research 35 11336535
1998 Regional distribution of [35S]2'-deoxy 5'-O-(1-thio) ATP binding sites and the P2Y1 messenger RNA within the chick brain. Neuroscience 35 9579787
2006 Mitochondrial calcium transport is regulated by P2Y1- and P2Y2-like mitochondrial receptors. Journal of cellular biochemistry 34 16795051
2005 Evidence for the existence of P2Y1,2,4 receptor subtypes in HEK-293 cells: reactivation of P2Y1 receptors after repetitive agonist application. Naunyn-Schmiedeberg's archives of pharmacology 34 16025270
2018 Astroglial Ca2+-Dependent Hyperexcitability Requires P2Y1 Purinergic Receptors and Pannexin-1 Channel Activation in a Chronic Model of Epilepsy. Frontiers in cellular neuroscience 33 30542266
2014 Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut. Proceedings of the National Academy of Sciences of the United States of America 33 25341729
2016 Dual Modulation of Nociception and Cardiovascular Reflexes during Peripheral Ischemia through P2Y1 Receptor-Dependent Sensitization of Muscle Afferents. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 26740646
1999 Benzoyl ATP is an antagonist of rat and human P2Y1 receptors and of platelet aggregation. Biochemical and biophysical research communications 32 10066429
2010 The purinergic P2Y1 receptor supports leptin secretion in adipose tissue. Endocrinology 31 20185765
2008 Novel consequences of voltage-dependence to G-protein-coupled P2Y1 receptors. British journal of pharmacology 31 18414379
2008 Development of selective high affinity antagonists, agonists, and radioligands for the P2Y1 receptor. Combinatorial chemistry & high throughput screening 31 18673269
2004 Regulation of P2Y1 receptor-mediated signaling by the ectonucleoside triphosphate diphosphohydrolase isozymes NTPDase1 and NTPDase2. Molecular pharmacology 31 15496502
2003 Enhanced P2Y1 receptor expression in the brain after sensitisation with d-amphetamine. Psychopharmacology 31 12652343
2017 Distinct Signaling Patterns of Allosteric Antagonism at the P2Y1 Receptor. Molecular pharmacology 30 28864555
2013 ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice. The European journal of neuroscience 30 24304101
2004 Subtype specific internalization of P2Y1 and P2Y2 receptors induced by novel adenosine 5'-O-(1-boranotriphosphate) derivatives. British journal of pharmacology 30 15197109
1997 Changes in P2Y1 nucleotide receptor activity during the development of rat salivary glands. The American journal of physiology 30 9142866
2012 Identification of contractile P2Y1, P2Y6, and P2Y12 receptors in rat intrapulmonary artery using selective ligands. The Journal of pharmacology and experimental therapeutics 29 22991416
2006 The enteric purinergic P2Y1 receptor. Current opinion in pharmacology 29 16934527
2007 P2Y1 gene deficiency protects from renal disease progression and capillary rarefaction during passive crescentic glomerulonephritis. Journal of the American Society of Nephrology : JASN 28 17215444
2004 Co-localization of P2Y1 receptor and NTPDase1/CD39 within caveolae in human placenta. European journal of histochemistry : EJH 28 15590415
1996 A guanine nucleotide-independent inwardly rectifying cation permeability is associated with P2Y1 receptor expression in Xenopus oocytes. The Journal of biological chemistry 28 8910562
2016 The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys. Journal of thrombosis and thrombolysis 27 26660522
2006 Opposite diastereoselective activation of P2Y1 and P2Y11 nucleotide receptors by adenosine 5'-O-(alpha-boranotriphosphate) analogues. British journal of pharmacology 27 16953187
2004 2,2'-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding. Biochemical pharmacology 27 15193995
2009 Extracellular ATP inhibits chloride channels in mature mammalian skeletal muscle by activating P2Y1 receptors. The Journal of physiology 26 19805741
2007 Stimulation of the P2Y1 receptor up-regulates nucleoside-triphosphate diphosphohydrolase-1 in human retinal pigment epithelial cells. The Journal of pharmacology and experimental therapeutics 26 17626796
2006 P2Y1 and P2Y2 receptor distribution varies along the human placental vascular tree: role of nucleotides in vascular tone regulation. The Journal of physiology 26 16543271
2019 MiR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes. Medical science monitor : international medical journal of experimental and clinical research 25 30778022
2017 PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 28578353
2014 Differential effects of P2Y1 deletion on glial activation and survival of photoreceptors and amacrine cells in the ischemic mouse retina. Cell death & disease 24 25077539
2011 The ADP receptor P2Y1 is necessary for normal thermal sensitivity in cutaneous polymodal nociceptors. Molecular pain 24 21310055
2009 P2X2, P2X4 and P2Y1 receptors elevate intracellular Ca2+ in mouse embryonic stem cell-derived GABAergic neurons. British journal of pharmacology 24 20050186
2014 Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium. Proceedings of the National Academy of Sciences of the United States of America 23 24550450
2009 beta-Arrestin-2 interaction and internalization of the human P2Y1 receptor are dependent on C-terminal phosphorylation sites. Molecular pharmacology 23 19741005
2011 P2Y1, P2Y6, and P2Y12 receptors in rat splenic sinus endothelial cells: an immunohistochemical and ultrastructural study. Histochemistry and cell biology 22 21879346