Affinage

P2RY12

P2Y purinoceptor 12 · UniProt Q9H244

Length
342 aa
Mass
39.4 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

P2RY12 is a Gαi-coupled G-protein-coupled receptor for ADP that suppresses adenylyl cyclase and, through this and parallel effectors, transduces purinergic signals in platelets, microglia, and vascular and immune cells (PMID:11104774, PMID:14573771). Pharmacological and reconstitution studies establish it as the clopidogrel target, originally designated the platelet P2T/P2TAC receptor: the clopidogrel active metabolite binds covalently and irreversibly to abolish ADP-induced signaling, while ATP acts as a low-affinity antagonist and 2-MeS-ADP is the most potent agonist (PMID:14573771, PMID:15199474). The receptor couples most robustly to Gαi2 (and to Gαi1/Gαi3 but not Gαo/Gαq), and beyond cyclase inhibition it drives two largely separable outputs — Gi-dependent PI3-kinase/Akt activation feeding MAP-kinase signaling and proliferation, and Gi-independent RhoA/Rho-kinase-dependent actin reorganization (PMID:14573771, PMID:14717977). Downstream of these effectors P2RY12 sustains diacylglycerol levels by inhibiting diacylglycerol kinase to potentiate PKC and Rap1b activation, amplifying platelet responses to thrombin/PAR signaling (PMID:18755689, PMID:20930120), and activates Rap1 to enhance osteoclast adhesion and bone resorption (PMID:22996695). Crystal structures in antagonist-bound (AZD1283) and full/partial agonist-bound (2MeSADP/2MeSATP) states reveal a class-A-atypical straight helix V, a dynamic helix III–ECL2 disulfide, and large-scale extracellular rearrangements required for agonist access, with agonist and non-nucleotide antagonist occupying only partially overlapping pockets (PMID:24670650, PMID:24784220). Receptor signaling is terminated by GRK2/GRK6-mediated desensitization and arrestin/NHERF1-dependent internalization through the receptor's PDZ-binding C-tail (PMID:15665114, PMID:22610101). In microglia, P2RY12 directs process chemotaxis toward ADP/ATP gradients and underlies blood–brain barrier closure, PANX1-coupled neurovascular regulation, NF-κB/NLRP3 inflammasome-driven cytokine production, p38 MAPK-dependent neuropathic pain, and modulation of neuronal excitability and general anesthesia sensitivity (PMID:18337420, PMID:26755608, PMID:31549730, PMID:31426845, PMID:34489419, PMID:37167975). In vascular smooth muscle cells it promotes senescence via sustained Ras activation and foam-cell formation by suppressing PI3K-AKT-mTOR-dependent autophagy, and in kidney macrophages it drives TGF-β/Smad3-mediated macrophage-to-myofibroblast transition (PMID:32160082, PMID:27534720, PMID:35791881). A dominant-negative ECL3 variant (R265P) that disrupts receptor homodimerization and signaling has been identified in a patient family, linking P2RY12 dysfunction to impaired platelet aggregation (PMID:29117459).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing that an orphan Gi-coupled receptor is the ADP target answered what receptor mediates ADP-driven inhibition of platelet adenylyl cyclase.

    Evidence Heterologous expression in CHO cells with adenylyl cyclase and Ca2+ assays plus mass-spectrometric ligand identification

    PMID:11104774

    Open questions at the time
    • G protein subtype selectivity not yet defined
    • downstream effectors beyond cyclase not addressed
  2. 2003 High

    Reconstitution with purified components defined G protein selectivity and confirmed the receptor as the pharmacological P2T/P2TAC and clopidogrel target.

    Evidence Sf9 expression, purification and lipid-vesicle reconstitution with Gα subunits; covalent binding of clopidogrel active metabolite in transfected CHO cells and platelets

    PMID:14573771 PMID:15199474

    Open questions at the time
    • physiological relevance of RGS4 enhancement not tested in vivo
    • covalent binding site on receptor not mapped
  3. 2004 Medium

    Pharmacological dissection separated Gi-dependent PI3K/Akt-MAPK proliferative signaling from Gi-independent RhoA/Rho-kinase actin remodeling, defining bifurcated downstream outputs.

    Evidence Stable CHO expression with pertussis toxin, PI3K and Rho-kinase inhibitors, proliferation and actin imaging readouts

    PMID:14717977

    Open questions at the time
    • single cell system, not validated in primary cells
    • mechanism of Gi-independent RhoA coupling unresolved
  4. 2005 High

    Identifying GRK2/GRK6 rather than PKC as the desensitizing kinases explained how P2Y12 signaling is terminated and distinguished it from P2Y1.

    Evidence Dominant-negative GRK mutants and siRNA in 1321N1 cells, platelet desensitization assays

    PMID:15665114

    Open questions at the time
    • arrestin recruitment downstream of GRK not directly demonstrated here
    • phosphosite mapping absent
  5. 2008 High

    Defining the DAG-kinase suppression mechanism showed how Gi-coupled P2Y12 amplifies Gq-driven PKC/Rap1b signaling in platelets, explaining its co-activation role.

    Evidence Human platelet aggregation, pleckstrin phosphorylation, Rap1b activation, DGK inhibition and phorbol ester bypass

    PMID:18755689

    Open questions at the time
    • DGK isoform involved not identified
    • link to RhoA pathway not addressed
  6. 2008 High

    Placing P2Y12 upstream of microglial p38 MAPK established a CNS signaling axis driving neuropathic pain, extending the receptor's role beyond platelets.

    Evidence Rat sciatic nerve ligation, in situ hybridization, intrathecal antagonist/antisense, agonist mimicry, p-p38 Western blot

    PMID:18337420

    Open questions at the time
    • direct biochemical link from P2Y12 to p38 not reconstituted
    • cell-autonomy within microglia not isolated
  7. 2010 Medium

    Epistasis with PAR knockouts positioned P2Y12 as a thrombin/PAR-independent amplifier in hemostasis and downstream of PARs in arterial thrombosis.

    Evidence P2ry12-/- and PAR-knockout mice, ex vivo aggregation, carotid thrombosis and intravital microscopy

    PMID:20930120

    Open questions at the time
    • molecular crosstalk between PAR and P2Y12 pathways not defined
    • single lab
  8. 2012 High

    Genetic knockout revealed P2Y12 as the primary ADP receptor driving Rap1-dependent osteoclast resorption, broadening function to bone biology.

    Evidence P2ry12-/- mice, bone resorption and RAP1 assays, multiple in vivo osteolysis models, clopidogrel validation

    PMID:22996695

    Open questions at the time
    • effector linking Rap1 to integrin/adhesion not fully mapped
    • human osteoclast relevance untested
  9. 2012 Medium

    Mapping the NHERF1/arrestin ternary complex on the receptor C-tail explained the trafficking mechanism for agonist-induced internalization.

    Evidence Co-IP, internalization assays, PDZ-motif mutant constructs and in vitro binding

    PMID:22610101

    Open questions at the time
    • single lab without reciprocal in vivo validation
    • fate of internalized receptor not tracked
  10. 2014 High

    High-resolution crystal structures in antagonist- and agonist-bound states defined the ligand-binding architecture and the unprecedented extracellular rearrangement required for agonist access.

    Evidence X-ray crystallography of AZD1283-, 2MeSADP- and 2MeSATP-bound human P2Y12R with docking

    PMID:24670650 PMID:24784220

    Open questions at the time
    • no active-state G-protein-bound structure
    • dynamics of disulfide and helix V not captured in solution
  11. 2015 Medium

    Showing M2-polarization-associated P2Y12 upregulation and neuronal cAMP/ryanodine-coupled Ca2+ signaling extended the receptor's signaling repertoire across CNS cell types.

    Evidence Human microglia M1/M2 cultures with calcium imaging and migration assays; rat trigeminal neuron calcium imaging with pharmacological dissection

    PMID:25821842 PMID:25987295

    Open questions at the time
    • in vivo relevance of M2 upregulation untested
    • neuronal P2Y12 expression contribution versus microglial unclear
  12. 2016 High

    Live imaging tied microglial P2RY12-mediated chemotaxis to blood–brain barrier closure, establishing a vascular-protective CNS function.

    Evidence Two-photon imaging in P2RY12-/- and clopidogrel-treated mice after laser-induced BBB breakdown

    PMID:26755608

    Open questions at the time
    • molecular effectors of process motility not defined
    • relationship to inflammatory signaling unaddressed
  13. 2016 High

    Two vascular smooth muscle studies established P2Y12 as a driver of foam-cell formation via PI3K-AKT-mTOR autophagy suppression and of senescence via sustained Ras activation.

    Evidence ApoE-/- and stretch models, siRNA and pharmacological inhibition, phosphoproteomics, ATG5/mTOR epistasis, Ras activation assays; P2ry12-/- mice

    PMID:27534720 PMID:32160082

    Open questions at the time
    • link between ADP source and chronic receptor activation in vivo incomplete
    • whether Ras and mTOR arms are connected unknown
  14. 2017 Medium

    A patient-derived dominant-negative ECL3 variant (R265P) revealed that homodimerization is required for receptor function and links P2Y12 defects to a bleeding phenotype.

    Evidence Family sequencing, mutant overexpression, surface expression and Gi signaling assays, dominant-negative co-expression, platelet aggregometry

    PMID:29117459

    Open questions at the time
    • structural basis of dimer interface not directly resolved
    • single family/lab
  15. 2019 High

    Microglial knockout work connected P2Y12 to NF-κB/NLRP3 inflammasome-driven cytokine output and to regulation of hippocampal neuronal excitability and innate fear.

    Evidence P2Y12-deficient microglia with siRNA and antagonist, NF-κB reporter/cytokine ELISA/caspase-1; constitutive and inducible conditional knockouts with behavior, c-fos and patch clamp

    PMID:31426845 PMID:31549730

    Open questions at the time
    • mechanism coupling P2Y12 to NLRP3 priming versus activation unclear
    • how microglial signaling alters neuronal excitability not defined molecularly
  16. 2021 High

    Studies defined a PANX1-P2RY12 axis for neurovascular regulation and showed NOD2-driven P2Y12 upregulation underlies platelet hyperactivity in sepsis.

    Evidence P2RY12-/- and PANX1-/- mice with two-photon imaging and blood-flow measures; septic patient and CLP platelets, NOD2-/- mice, pAkt/pVASP readouts

    PMID:34489419 PMID:34748820

    Open questions at the time
    • purine species and source linking PANX1 to P2RY12 not fully resolved
    • transcriptional control of P2Y12 in platelets versus inheritance unclear
  17. 2022 Medium

    Convergent studies extended P2Y12 to TGF-β/Smad3-driven macrophage-to-myofibroblast transition in renal fibrosis and to platelet CD40L-dependent anti-tumor CD8+ T cell responses.

    Evidence LysM lineage tracing, UUO model, scRNA-seq, siRNA/clopidogrel and Smad3 analysis; P2Y12 depletion with WT versus CD40L-/- platelet transfusion in NAFLD-HCC models

    PMID:35791881 PMID:36055226

    Open questions at the time
    • direct receptor-to-Smad3 coupling mechanism not reconstituted
    • single-lab findings for each context
  18. 2023 High

    Microglial studies linked P2Y12 to Arp2-dependent podosome/filopodia-mediated Tau degradation and to control of general anesthesia depth, broadening its CNS effector and behavioral roles.

    Evidence N9 microglia imaging with actin scaffold colocalization and antagonist; microglial conditional knockout, depletion/repopulation and chemogenetics with anesthesia behavioral readouts and scRNA-seq

    PMID:37167975 PMID:37221563

    Open questions at the time
    • molecular link from P2Y12 to Arp2/podosome machinery not defined
    • how microglial P2Y12 influences anesthetic targets mechanistically unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single Gαi-coupled receptor is wired to such divergent effector outputs (Ras, mTOR-autophagy, Smad3, NLRP3, RhoA, podosome assembly) in a cell-type-specific manner, and how its active-state G-protein-coupled conformation is structured, remains unresolved.
  • no active-state ternary (receptor–G protein) structure
  • cell-type-specific determinants of effector selection unknown
  • direct biochemical links between receptor and several downstream pathways not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 2 R-HSA-9612973 Autophagy 1
Partners
ARRB (ARRESTIN)GRK2GRK6NHERF1PANX1
Complex memberships
P2Y12 homodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 SP1999 (P2RY12) is a Gαi-coupled receptor for ADP; ADP inhibits forskolin-stimulated adenylyl cyclase activity through selective activation of this receptor with an EC50 of 60 nM. The rank order of potency was 2-MeS-ATP = 2-MeS-ADP > ADP > other nucleotides. ATP showed no agonist activity but acted as a low-affinity antagonist. Heterologous expression in CHO cells, adenylyl cyclase inhibition assay, Ca2+ mobilization assay with chimeric Gαq/i, mass spectrometry identification of purified ligand from rat spinal cord extracts The Journal of biological chemistry High 11104774
2003 Purified recombinant human P2Y12 receptor couples most robustly to Gαi2, and also effectively to Gαi1 and Gαi3, but shows little or no coupling to Gαo or Gαq. 2MeSADP is the most potent agonist (EC50 = 80 nM); ADP is ~1000-fold less potent. ATP acts as a low-affinity antagonist. RGS4 markedly enhances agonist-stimulated GTPase activity. Baculovirus expression in Sf9 cells, protein purification, reconstitution in lipid vesicles with purified Gα subunits and Gβ1γ2, steady-state GTPase assay Molecular pharmacology High 14573771
2003 The active metabolite of clopidogrel binds covalently and irreversibly to P2Y12 on platelets and in stably transfected CHO cells, blocking 33P-2MeS-ADP binding and ADP-induced adenylyl cyclase downregulation. P2Y12 corresponds to the previously designated 'P2T/P2TAC' receptor. Stable expression in CHO cells, radioligand binding assay (33P-2MeS-ADP), adenylyl cyclase inhibition assay, pharmacological profiling with clopidogrel active metabolite Seminars in vascular medicine Medium 15199474
2005 P2Y12 desensitization is mediated by G protein-coupled receptor kinases (GRK2 and GRK6), but not by protein kinase C. This is distinct from P2Y1, whose desensitization is largely dependent on PKC activity. Both GRKs are endogenously expressed in platelets. Transient overexpression of dominant-negative GRK mutants and siRNA knockdown in 1321N1 cells; platelet aggregation desensitization assays in human platelets Blood High 15665114
2004 P2Y12 receptor activation in CHO cells triggers two distinct signaling pathways: (1) Gi-dependent activation of PI3-kinase/Akt upstream of MAP-kinases leading to cell proliferation, with partial contribution via transactivation of PDGF-Rβ; (2) Gi-independent RhoA/Rho-kinase activation leading to actin cytoskeleton reorganization. Both pathways are blocked by the active metabolite of clopidogrel. Stable expression in CHO cells, pharmacological inhibition (pertussis toxin, PI3K inhibitors, Rho-kinase inhibitors), cell proliferation assays, actin cytoskeleton imaging Journal of thrombosis and haemostasis : JTH Medium 14717977
2008 The Gi-coupled P2Y12 receptor regulates diacylglycerol (DAG)-mediated signaling in platelets: P2Y12 stimulation inhibits diacylglycerol kinase-mediated phosphorylation of DAG to phosphatidic acid, thereby sustaining DAG levels and enhancing PKC activation and Rap1b activation downstream of Gq-coupled receptors. This effect requires PI3-kinase rather than adenylyl cyclase inhibition. Platelet aggregation assays, pleckstrin phosphorylation (PKC readout), Rap1b activation assay, diacylglycerol kinase inhibition, pharmacological blockade of P2Y1 and P2Y12 receptors, phorbol ester bypass experiments The Journal of biological chemistry High 18755689
2008 P2Y12 mRNA and protein are upregulated in spinal cord microglia following partial sciatic nerve ligation, peaking at day 3. P2Y12 activation by ADP/hydrolyzed ATP acts as a gateway for p38 MAPK phosphorylation in spinal microglia; intrathecal P2Y12 antagonist or antisense knockdown suppressed p38 activation and neuropathic pain behaviors. Intrathecal P2Y12 agonist in naive rats mimicked nerve injury-induced p38 activation. Rat partial sciatic nerve ligation model, double-label in situ hybridization/immunohistochemistry, intrathecal pharmacological blockade, antisense knockdown, Western blot for p-p38 The Journal of neuroscience : the official journal of the Society for Neuroscience High 18337420
2012 P2RY12 is the primary ADP receptor in osteoclasts (OCs). ADP stimulation of P2RY12 activates RAP1 and enhances OC adhesion and bone resorptive activity. P2ry12-/- OCs show intact differentiation but diminished resorptive function and blunted ADP-induced RAP1 activation. P2ry12-/- mice are partially protected from age-associated bone loss, arthritis-induced osteolysis, tumor-induced osteolysis, and ovariectomy-induced osteoporosis. P2ry12-/- mice, bone resorption assays, RAP1 activation assay, integrin β3 knockout comparison, in vivo bone loss models (FeCl3 arthritis, tumor, ovariectomy), clopidogrel pharmacological treatment The Journal of clinical investigation High 22996695
2012 P2Y12 receptor internalization requires interaction of its PDZ-binding motif with NHERF1. Prior to agonist stimulation, NHERF1 binds directly to the receptor C-tail. Upon agonist stimulation, NHERF1 no longer binds the receptor directly but instead interacts via arrestin as a scaffold, promoting NHERF1-dependent receptor internalization. Co-immunoprecipitation, mammalian cell overexpression, receptor internalization assays, dominant-negative and mutant receptor constructs, in vitro binding assays The Journal of biological chemistry Medium 22610101
2014 Crystal structure of human P2Y12R at 2.6 Å resolution in complex with antagonist AZD1283 reveals: (1) a distinct straight conformation of helix V unique among class A GPCRs; (2) absence of the conserved disulfide bridge between helix III and ECL2 (appears dynamic); (3) a non-nucleotide ligand-binding site with an adjacent pocket suggesting both pockets are required for dinucleotide binding. X-ray crystallography at 2.6 Å resolution Nature High 24670650
2014 Crystal structures of human P2Y12R bound to full agonist 2MeSADP (2.5 Å) and partial agonist 2MeSATP (3.1 Å) reveal large-scale conformational rearrangements in the extracellular region required for agonist access to the binding pocket — the first example of such rearrangement for a GPCR. Agonist and non-nucleotide antagonist (AZD1283) adopt different orientations with only partially overlapping binding pockets. X-ray crystallography at 2.5 Å and 3.1 Å resolution, docking studies, comparison with antagonist-bound structure Nature High 24784220
2016 P2RY12-mediated chemotaxis of microglial processes is required for rapid closure of the blood-brain barrier following laser-induced BBB breakdown. Both pharmacological inhibition (clopidogrel) and genetic ablation of P2RY12 significantly diminished juxtavascular microglial process movement and failed to close laser-induced BBB openings. Two-photon live imaging of microglial processes in mice, laser-induced BBB opening, P2RY12 genetic knockout mice, clopidogrel pharmacological inhibition, fluorescent tracer BBB permeability assay Proceedings of the National Academy of Sciences of the United States of America High 26755608
2016 ADP activation of P2Y12 receptor in VSMCs inhibits macroautophagy via the PI3K-AKT-MTOR pathway, blocking LC3 maturation, SQSTM1 degradation, and autophagosome formation, thereby reducing cholesterol efflux and promoting foam cell formation. P2Y12 receptor inhibition promotes VSMC autophagy and cholesterol efflux in an ATG5-dependent manner. ApoE-/- mouse atherosclerosis model, siRNA knockdown and pharmacological inhibition of P2Y12R, phosphoproteomic analysis, Western blot for LC3/SQSTM1, autophagosome TEM, cholesterol efflux assay, rapamycin rescue experiment, ATG5 knockdown epistasis Autophagy High 32160082
2016 Sustained ADP/P2RY12 signaling in vascular smooth muscle cells induces senescence via sustained Ras activation. Mechanical stretch increases ADP release from SMCs; P2ry12 genetic knockout in mice protects against SMC senescence, inflammation, and TAAD formation and rupture. Pharmacological Ras inhibition also protected against SMC senescence. P2ry12-/- mice, excessive mechanical stretch model, SA-β-gal staining, senescence marker Western blotting, HPLC and luciferin-luciferase ADP measurement, Ras activation assay, pharmacological Ras inhibition Journal of molecular and cellular cardiology Medium 27534720
2019 ADP acting on microglial P2Y12 receptor activates NF-κB signaling and potentiates NLRP3 inflammasome activation, leading to enhanced IL-1β and IL-6 production. Mechanistically, ADP altered mitochondrial membrane potential in combination with ATP and increased caspase-1 positive cells through P2Y12 receptor. P2Y12 receptor-deficient microglia, siRNA knockdown, PSB0739 pharmacological blockade, NF-κB reporter assay, IL-1β/IL-6 ELISA, caspase-1 flow cytometry, mitochondrial membrane potential assay European journal of immunology Medium 31549730
2019 Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear behavior. Constitutive and induced conditional P2Y12R knockout mice exhibited increased innate fear and elevated CA1 neuronal excitability (assessed by c-fos expression and whole-cell patch clamp). Microglial process chemotaxis toward ADP/ATP gradients is mediated by P2Y12R. Conditional microglial P2Y12R knockout mice (CX3CR1-Cre and CX3CR1-CreER), behavioral testing (elevated plus maze), c-fos immunostaining, whole-cell patch clamp recording in ventral hippocampus CA1 Molecular brain High 31426845
2021 P2RY12 receptors on capillary-associated microglia (CAMs) regulate vascular structure and function under the control of purines released from pannexin-1 (PANX1) channels. P2RY12-/- and PANX1-/- mice phenocopied microglial depletion in causing capillary dilation, increased blood flow, and impaired vasodilation, establishing a PANX1-P2RY12 coupling mechanism for neurovascular regulation. P2RY12-/- and PANX1-/- mice, microglial depletion and repopulation, two-photon live imaging, blood flow measurement, ultrastructural analysis, spatio-temporal morphological characterization Nature communications High 34489419
2022 P2Y12 receptor is expressed by macrophages in fibrosing kidneys (>82% of P2Y12-expressing cells are macrophage-origin); activation by TGF-β1 induces P2Y12 expression and promotes macrophage-to-myofibroblast transition (MMT) via the Smad3-dependent signaling pathway. Silencing or pharmacological inhibition of P2Y12 blocked TGF-β/Smad3-mediated MMT and progressive renal fibrosis. LysM-Cre/Rosa Tomato lineage tracing mice, UUO model, P2Y12 siRNA knockdown, clopidogrel treatment, single-cell RNA sequencing, α-SMA/CD68 co-immunostaining, in vitro TGF-β1 stimulation, Smad3 pathway analysis Molecular therapy : the journal of the American Society of Gene Therapy High 35791881
2017 P2Y12R homodimerization is critical for receptor function and signaling. A dominant negative variant R265P in extracellular loop 3 (EL3) disrupts the binding pocket conformation, reduces agonist-stimulated signaling and receptor surface loss, and acts in a dominant negative manner by impairing wild-type homodimer function. R265 is one of four residues required for receptor functional integrity. Next-generation sequencing/Sanger sequencing of patient family, mammalian cell overexpression of R265P mutant, receptor surface expression (flow cytometry/Western blot), Gi signaling assays, dominant negative co-expression experiments, platelet aggregometry, P2RY12 cDNA cloning from patients Journal of thrombosis and haemostasis : JTH Medium 29117459
2023 Microglial P2Y12R mediates microglial process chemotaxis toward Tau oligomers and facilitates degradation of Tau deposits via Arp2-associated podosome and filopodia formation. P2Y12 receptors colocalize with F-actin-rich podosomes and filopodia during Tau-deposit degradation. Blockage of P2Y12 signaling decreased microglial migration and Tau-deposit degradation. N9 microglia cell culture, fluorescence microscopy for actin microstructures (podosome, filopodia, uropod), P2Y12 pharmacological blockade, colocalization with Arp2/TKS5/WASP scaffold proteins, Tau oligomer treatment Cell & bioscience Medium 37221563
2023 Microglial P2Y12R mediates microglial participation in general anesthesia. Blocking P2Y12R pharmacologically or genetic ablation of P2Y12R specifically in microglia (CX3CR1-Cre) shortened duration of loss of righting reflex (unconsciousness) from multiple anesthetics and attenuated anesthesia-accompanying analgesia and hypothermia. Microglial depletion, microglial repopulation, chemogenetic activation, conditional P2Y12R knockout (CX3CR1-Cre), pharmacological P2Y12R blockade, single-cell RNA sequencing of anesthesia-affected transcriptional programs Current biology : CB High 37167975
2022 Platelet P2Y12-dependent CD40L release mediates anti-tumor activity of platelets in NAFLD-associated HCC. Pharmacological inhibition or genetic depletion of P2Y12 abrogated CD40L release from platelets, reduced CD8+ T cell activation via the CD40 receptor, and accelerated HCC growth. P2Y12 genetic depletion, pharmacological inhibition, in vivo transfusion of WT vs CD40L-/- platelets, HCC tumor models in NAFLD mice, liver metastasis models Cancer cell Medium 36055226
2010 P2ry12 functions in thrombin/PAR-independent pathways in vivo for hemostasis models, while in arterial thrombosis models PAR signaling was dominant. P2ry12 acts downstream of PARs to amplify platelet responses to thrombin ex vivo. P2ry12+/- platelets showed partially decreased ADP responses resembling clopidogrel-treated human platelets. Par3-/-:P2ry12-/- double-mutant mice showed combined additive protection against carotid thrombosis. P2ry12-/- and PAR knockout mice, platelet aggregation assays ex vivo, carotid artery thrombosis models with varying FeCl3 injury levels, intravital microscopy Proceedings of the National Academy of Sciences of the United States of America Medium 20930120
2015 P2Y12 expression is increased in alternatively activated (M2) human microglia compared to resting or classically activated (M1) microglia. M2 microglia show increased ADP-induced calcium responses that are blocked by selective P2Y12 antagonism. P2Y12 antagonism decreases migratory and inflammatory responses in human microglia upon nucleotide exposure; no effects were observed in human monocytes or macrophages. In vitro human microglia activation (M1/M2 conditions), flow cytometry, calcium imaging, P2Y12 antagonist pharmacological blockade, migration assays, in situ immunohistochemistry of MS and parasitic CNS infection brain samples Neurology(R) neuroimmunology & neuroinflammation Medium 25821842
2021 NOD2 activation in sepsis upregulates platelet P2Y12 expression via the RIP2/NF-κB/P65 pathway, leading to constitutive P2Y12 activation (evidenced by enhanced pAkt and impaired pVASP in resting platelets) and platelet hyperactivity. NOD2 deficiency attenuated sepsis-induced platelet P2Y12 high expression, hyperactivity, and thrombosis. Septic patient platelets, CLP mouse model, NOD2-/- mice, Western blot (pAkt, pVASP as P2Y12 signaling readouts), platelet aggregation assays, NF-κB pathway analysis Biochemical pharmacology Medium 34748820
2015 P2Y12 receptor activation in trigeminal ganglion neurons mediates ADP-induced intracellular Ca2+ release from ryanodine-sensitive stores via a cAMP-dependent pathway. In the absence of extracellular Ca2+, ryanodine receptor inhibitors blocked 2-MeS-ADP-induced Ca2+ increases, and adenylate cyclase inhibition mimicked agonist effects. Rat TG neuron culture, immunofluorescence, calcium imaging with selective P2Y12 antagonists, ryanodine receptor blockers, SERCA inhibitor, adenylate/phosphodiesterase inhibitors, extracellular calcium chelation Neuroscience research Medium 25987295

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 317 24670650
2017 International Expert Consensus on Switching Platelet P2Y12 Receptor-Inhibiting Therapies. Circulation 307 29084738
2016 Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proceedings of the National Academy of Sciences of the United States of America 282 26755608
2009 Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovascular therapeutics 271 19604248
2014 Agonist-bound structure of the human P2Y12 receptor. Nature 265 24784220
2008 P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 247 18337420
2005 Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Seminars in thrombosis and hemostasis 246 15852221
2021 Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice. Nature communications 240 34489419
2003 Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 197 14603465
2000 ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. The Journal of biological chemistry 168 11104774
2020 The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy 161 32160082
2021 Microglia and Neuroinflammation: What Place for P2RY12? International journal of molecular sciences 158 33561958
2015 P2Y12 expression and function in alternatively activated human microglia. Neurology(R) neuroimmunology & neuroinflammation 154 25821842
2006 Biology and pharmacology of the platelet P2Y12 receptor. Current pharmaceutical design 146 16611109
2015 Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nature reviews. Cardiology 145 26283269
2010 The platelet P2Y₁₂ receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 137 20966167
2022 Co-expression patterns of microglia markers Iba1, TMEM119 and P2RY12 in Alzheimer's disease. Neurobiology of disease 136 35247551
2005 P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood 133 15665114
2015 P2Y12 receptors: structure and function. Journal of thrombosis and haemostasis : JTH 130 26149010
2013 Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC. Cardiovascular interventions 128 24262612
2015 Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes. Thrombosis and haemostasis 113 25904241
2015 Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain. Brain, behavior, and immunity 108 26576724
2020 Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer's Disease Brains. International journal of molecular sciences 107 31968618
2013 Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs 105 24114622
2012 P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic signalling 105 22528678
2016 Effects of P2Y12 receptor antagonists beyond platelet inhibition--comparison of ticagrelor with thienopyridines. British journal of pharmacology 91 26758983
2012 P2Y12 platelet inhibition in clinical practice. Journal of thrombosis and thrombolysis 89 22183178
2001 The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 89 11454254
2019 Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear in mice. Molecular brain 87 31426845
2016 P2Y12 Receptor Modulates Sepsis-Induced Inflammation. Arteriosclerosis, thrombosis, and vascular biology 86 27055904
2012 The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. The Journal of clinical investigation 86 22996695
2015 Effect of P2Y12 inhibitors on inflammation and immunity. Thrombosis and haemostasis 85 26156883
2020 P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation. International journal of molecular sciences 83 32092903
2014 Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery. British journal of anaesthesia 80 25209096
2022 P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition. Molecular therapy : the journal of the American Society of Gene Therapy 77 35791881
2003 P2Y12, a new platelet ADP receptor, target of clopidogrel. Seminars in vascular medicine 77 15199474
2011 P2Y12 receptor in platelet activation. Platelets 76 21231822
2014 Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents. Neurobiology of disease 74 24971933
2016 Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thrombosis and haemostasis 72 27975100
2019 Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 31597724
2022 Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD. Cancer cell 67 36055226
2006 Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. Journal of thrombosis and thrombolysis 67 17111196
2017 Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade. Acta neuropathologica communications 65 28073370
2003 Purification and functional reconstitution of the human P2Y12 receptor. Molecular pharmacology 65 14573771
2009 P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. Cerebral cortex (New York, N.Y. : 1991) 62 19783848
2021 Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor. Brain communications 60 33644757
2015 Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion. BMC cancer 59 26353776
2003 Anticoagulants (thrombin inhibitors) and aspirin synergize with P2Y12 receptor antagonism in thrombosis. Circulation 59 14597584
2019 Extracellular ADP augments microglial inflammasome and NF-κB activation via the P2Y12 receptor. European journal of immunology 56 31549730
2004 Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor. Journal of thrombosis and haemostasis : JTH 52 14717977
2020 Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists. Clinical pharmacokinetics 50 32056160
2018 P2Y12 Receptors in Tumorigenesis and Metastasis. Frontiers in pharmacology 50 29456511
2014 The role of P2Y₁₂ receptor and activated platelets during inflammation. Current drug targets 50 24845219
2008 The Gi-coupled P2Y12 receptor regulates diacylglycerol-mediated signaling in human platelets. The Journal of biological chemistry 48 18755689
2018 Antithrombotic P2Y12 receptor antagonists: recent developments in drug discovery. Drug discovery today 47 30291899
2014 Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors. Journal of thrombosis and haemostasis : JTH 47 24406062
2014 Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors. Thrombosis and haemostasis 45 24763899
2017 Advocating cardiovascular precision medicine with P2Y12 receptor inhibitors. European heart journal. Cardiovascular pharmacotherapy 39 28204303
2010 Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. Proceedings of the National Academy of Sciences of the United States of America 39 20930120
2004 Functional expression of human and mouse P2Y12 receptors in Saccharomyces cerevisiae. Biochemical and biophysical research communications 37 15464998
2015 Personalized antiplatelet therapy with P2Y12 receptor inhibitors: benefits and pitfalls. Postepy w kardiologii interwencyjnej = Advances in interventional cardiology 36 26677375
2011 Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. Journal of thrombosis and haemostasis : JTH 36 21261805
2011 Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors. Thrombosis and haemostasis 36 21479343
2016 Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection. Journal of molecular and cellular cardiology 35 27534720
2021 P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers. Frontiers in oncology 34 34589424
2020 Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype. International journal of molecular sciences 32 33142937
2018 The role of P2Y12 receptor in ischemic stroke of atherosclerotic origin. Cellular and molecular life sciences : CMLS 32 30302530
2010 Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist. The Annals of pharmacotherapy 32 20124464
2015 Expression and function of purinergic P2Y12 receptors in rat trigeminal ganglion neurons. Neuroscience research 31 25987295
2012 Arrestin scaffolds NHERF1 to the P2Y12 receptor to regulate receptor internalization. The Journal of biological chemistry 31 22610101
2023 Microglia modulate general anesthesia through P2Y12 receptor. Current biology : CB 29 37167975
2011 BF061, a novel antiplatelet and antithrombotic agent targeting P2Y₁₂ receptor and phosphodiesterase. Thrombosis and haemostasis 28 21946947
2017 Role of P2Y12 Receptor in Thrombosis. Advances in experimental medicine and biology 27 27628007
2013 Molecular mechanisms of platelet P2Y(12) receptor regulation. Biochemical Society transactions 27 23356287
2012 Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 27 22010907
2023 The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges. International journal of molecular sciences 26 37047682
2023 Microglia degrade Tau oligomers deposit via purinergic P2Y12-associated podosome and filopodia formation and induce chemotaxis. Cell & bioscience 26 37221563
2021 The Function and Regulation of Platelet P2Y12 Receptor. Cardiovascular drugs and therapy 26 34319489
2018 Montelukast inhibits RANKL‑induced osteoclast formation and bone loss via CysLTR1 and P2Y12. Molecular medicine reports 26 29916540
2017 Structure, Pharmacology and Roles in Physiology of the P2Y12 Receptor. Advances in experimental medicine and biology 26 28921447
2023 P2Y12 Inhibition Suppresses Proinflammatory Platelet-Monocyte Interactions. Thrombosis and haemostasis 25 36630990
2015 Purinergic P2Y12 Receptor Activation in Eosinophils and the Schistosomal Host Response. PloS one 25 26448282
2016 P2Y12 receptor blockade synergizes strongly with nitric oxide and prostacyclin to inhibit platelet activation. British journal of clinical pharmacology 24 26561399
2023 Tau aggregates improve the Purinergic receptor P2Y12-associated podosome rearrangements in microglial cells. Biochimica et biophysica acta. Molecular cell research 23 37061007
2019 Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function. JCI insight 23 31434806
2006 Molecular modeling of purinergic receptor P2Y12 and interaction with its antagonists. Journal of molecular graphics & modelling 23 17110146
2023 Pharmacogenetics of P2Y12 receptor inhibitors. Pharmacotherapy 22 36588476
2016 P2Y12 Receptor Antagonists and Morphine: A Dangerous Liaison? Circulation. Cardiovascular interventions 22 27586412
2009 Platelet P2Y12 receptor inhibition by thienopyridines: status and future. Expert opinion on investigational drugs 22 19678800
2024 Gualou-Xiebai herb pair and its active ingredients act against atherosclerosis by suppressing VSMC-derived foam cell formation via regulating P2RY12-mediated lipophagy. Phytomedicine : international journal of phytotherapy and phytopharmacology 21 38518636
2023 The role of platelet P2Y12 receptors in inflammation. British journal of pharmacology 21 37771103
2007 Expression and functional characterization of P2Y1 and P2Y12 nucleotide receptors in long-term serum-deprived glioma C6 cells. The FEBS journal 21 17355284
2017 Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding. Journal of thrombosis and haemostasis : JTH 20 29117459
2016 P2Y12-ADP receptor antagonists: Days of future and past. World journal of cardiology 20 27231519
2021 NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis. Biochemical pharmacology 19 34748820
2016 Transition strategies from cangrelor to oral platelet P2Y12 receptor antagonists. Coronary artery disease 18 26444255
2009 Cangrelor: a novel P2Y12 receptor antagonist. Expert opinion on investigational drugs 18 19604122
2017 Associations between P2RY12 gene polymorphisms and risks of clopidogrel resistance and adverse cardiovascular events after PCI in patients with acute coronary syndrome. Medicine 17 28383427
2018 P2Y12 receptor inhibitors: an evolution in drug design to prevent arterial thrombosis. Expert opinion on drug metabolism & toxicology 15 29338536
2014 Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population. Molecular biology reports 15 25106522

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