Top ▲

P2Y12 receptor

Click here for help

Target not currently curated in GtoImmuPdb

Target id: 328

Nomenclature: P2Y12 receptor

Family: P2Y receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 342 3q25.1 P2RY12 purinergic receptor P2Y12 7,29
Mouse 7 347 3 D P2ry12 purinergic receptor P2Y, G-protein coupled 12 47
Rat 7 343 2q26 P2ry12 purinergic receptor P2Y12 29,53
Previous and Unofficial Names Click here for help
SP1999 | P2YADP | HORK3 | P2Y purinoceptor 12 | P2Y12 platelet ADP receptor | purinergic receptor P2Y
Database Links Click here for help
Specialist databases
GPCRdb p2y12_human (Hs), p2y12_mouse (Mm), p2y12_rat (Rn)
Other databases
Alphafold Q9H244 (Hs), Q9CPV9 (Mm), Q9EPX4 (Rn)
ChEMBL Target CHEMBL2001 (Hs), CHEMBL2188 (Rn)
DrugBank Target Q9H244 (Hs)
Ensembl Gene ENSG00000169313 (Hs), ENSMUSG00000036353 (Mm), ENSRNOG00000013902 (Rn)
Entrez Gene 64805 (Hs), 70839 (Mm), 64803 (Rn)
Human Protein Atlas ENSG00000169313 (Hs)
KEGG Gene hsa:64805 (Hs), mmu:70839 (Mm), rno:64803 (Rn)
OMIM 600515 (Hs)
Orphanet ORPHA124046 (Hs)
Pharos Q9H244 (Hs)
RefSeq Nucleotide NM_022788 (Hs), NM_027571 (Mm), NM_022800 (Rn)
RefSeq Protein NP_073625 (Hs), NP_081847 (Mm), NP_073637 (Rn)
SynPHARM 4077 (in complex with 2MeSADP)
4083 (in complex with [3H]2MeSADP)
UniProtKB Q9H244 (Hs), Q9CPV9 (Mm), Q9EPX4 (Rn)
Wikipedia P2RY12 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the human P2Y12 receptor in complex with an antithrombotic drug
PDB Id:  4NTJ
Ligand:  AZD1283
Resolution:  2.62Å
Species:  Human
References:  63
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of P2Y12 receptor in complex with 2MeSATP
PDB Id:  4PY0
Ligand:  2MeSATP
Resolution:  3.1Å
Species:  Human
References:  62
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of P2Y12 receptor in complex with 2MeSADP
PDB Id:  4PXZ
Ligand:  2MeSADP
Resolution:  2.5Å
Species:  Human
References:  62
Natural/Endogenous Ligands Click here for help
ADP
Potency order of endogenous ligands (Human)
ADP>ATP

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
2MeSADP Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 9.2 pKi 29
⤷ pKi 9.2 [29]
ADP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.9 pKi 29
⤷ pKi 5.9 [29]
ADPβS Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 8.6 pIC50 56
⤷ pIC50 8.6 [56]
[3H]2MeSADP Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist 7.5 – 9.6 pIC50 56
⤷ pIC50 7.5 – 9.6 (IC50 3.16x10-8 – 2.5x10-10 M) [56]
Agonist Comments
ATP, 2-meSATP and ATP-γ-S have been reported to both stimulate and antagonise the P2Y12 receptor. ATP and 2-meSATP have long been known to antagonise P2Y12 receptor-mediated inhibition of adenylyl cyclase in platelets [14,45]. In contrast, ATP, 2-meSATP and ATP-γ-S were prosposed to be P2Y12 agonists in studies on the recombinant receptor [56,61]. The agonism was abolished, however, under conditions when contaminating diphosphates were removed [34]. Thus it is likely that ATP, 2-meSATP and ATP-γ-S are P2Y12 antagonists or at most, weak partial agonists when the P2Y12 receptor is expressed at high levels. An in silico screening for endogenous ligands acting on the human P2Y12 receptor revealed cysteinylleukotrienes (CysLTs) and 5-phosphoribosyl 1-pyrophosphate (PRPP) as potential ligands. In CHO cells stably expressing P2Y12-Gα16 fusion proteins, CysLTE4 and PRPP appeared to act as agonists at the P2Y12 receptor [42]. These data were not supported, however, by a subsequent study, which found CysLTs to be inactive at the P2Y12 receptor [21]. Thus the interaction of CysLTs with the P2Y12 receptor is uncertain.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PSB-0739 Small molecule or natural product Hs Antagonist 9.8 pA2 27
⤷ pA2 9.8 [27]
ticagrelor Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.6 pKB 28
⤷ pKB 8.6 [28]
[3H]PSB-0413 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 8.3 – 8.5 pKd 17,43
⤷ pKd 8.3 – 8.5 (Kd 4.57x10-9 – 3.16x10-9 M) [17,43]
AR-C67085 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.2 pKd 35
⤷ pKd 8.2 [35]
ticagrelor Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.8 – 8.7 pKi 54,60
⤷ pKi 8.7 (Ki 1.99x10-9 M) [54]
Description: Binding data obtained using washed platelets in 96-well plates, with [125I]-P2Y12 antagonist as radioligand.
pKi 7.8 (Ki 1.4x10-8 M) [60]
compound 20o [PMID: 22984835] Small molecule or natural product Hs Antagonist 8.1 pKi 60
⤷ pKi 8.1 (Ki 7.7x10-9 M) [60]
AZD1283 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 8.0 pKi 2,63
⤷ pKi 8.0 [2,63]
PSB-0739 Small molecule or natural product Hs Antagonist 7.6 pKi 3
⤷ pKi 7.6 (Ki 2.49x10-8 M) [3]
clopidogrel (active metabolite) Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 6.9 pKi 26
⤷ pKi 6.9 [26]
compound 4 [PMID: 22984835] Small molecule or natural product Hs Antagonist 6.9 pKi 60
⤷ pKi 6.9 (Ki 1.39x10-7 M) [60]
pCMBS Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.9 pKi 26
⤷ pKi 5.9 [26]
cangrelor Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.0 – 9.4 pIC50 32,56
⤷ pIC50 9.4 (IC50 4x10-10 M) [32]
pIC50 8.0 [56]
regrelor Small molecule or natural product Hs Antagonist 7.9 pIC50 16
⤷ pIC50 7.9 [16]
ARL66096 Small molecule or natural product Hs Antagonist 7.9 pIC50 30-31
⤷ pIC50 7.9 [30-31]
BX 667 Small molecule or natural product Hs Antagonist 7.0 pIC50 48
⤷ pIC50 7.0 [48]
compound 4 [PMID: 23083103] Small molecule or natural product Hs Antagonist 6.9 pIC50 12
⤷ pIC50 6.9 [12]
compound 58l [PMID: 30843696] Small molecule or natural product Hs Antagonist 6.5 pIC50 38
⤷ pIC50 6.5 (IC50 2.94x10-7 M) [38]
Description: Antagonism of ADP-induced platelet aggregation in human platelet-rich plasma.
BX 048 Small molecule or natural product Hs Antagonist 6.5 pIC50 48
⤷ pIC50 6.5 [48]
INS49266 Small molecule or natural product Hs Antagonist 6.3 pIC50 16
⤷ pIC50 6.3 [16]
Ap4A Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.0 pIC50 39
⤷ pIC50 6.0 [39]
2MeSAMP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.4 pIC50 56
⤷ pIC50 5.4 [56]
R-138727 Small molecule or natural product Hs Antagonist 4.7 – 5.7 pIC50 24
⤷ pIC50 4.7 – 5.7 [24]
Antagonist Comments
A recent paper claimed that 2MeSAMP and Cangrelor (ARC69931MX), two widely used P2Y12 antagonists, interacted with an unidentified platelet G protein-coupled receptor to increase cAMP production and so inhibit platelet function. This inhibition was in addition to that derived from antagonism of P2Y12 receptors [55]. This claim was not supported, however, by a subsequent study, which found 2MeSAMP and Cangrelor to have no effect on platelet cAMP levels or protein kinase A activity in the absence of P2Y12 receptor stimulation. Furthermore, both were inactive in platelets obtained from P2Y12 knockout mice [59]. Elinogrel (PRT060128) is a patented high affinity antagonist [23].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
References:  7
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Adenylyl cyclase inhibition
Other - See Comments
Comments:  Gi family proteins. The intracellular pathways through which P2Y12 amplifies platelet responses include inhibition of cyclic AMP production, vasodilator-stimulated phosphoprotein (VASP) dephosphorylation, phosphoinositide 3 kinase (PI 3-K) and small GTPase Rap1b activation [22,50]. In some experimental systems, P2Y12/P2Y13 receptors were found to be coupled to [Ca2+]i increases. In particular, in microglial and satellite glial cells from trigeminal ganglia, the ADP-induced [Ca2+]i responses were significantly reduced after pretreatement with Cangrelor, an antagonist selective for P2Y12 and P2Y13, thus suggesting their activation may also contribute to ADP-mediated effects [6,11].
References: 
Tissue Distribution Click here for help
Platelets and brain tissues.
Species:  Human
Technique:  Northern blotting.
References:  29
Vascular smooth muscle cells
Species:  Human
Technique:  Real-time PCR
References:  58
Brain, heart, spleen, lung, liver and macrophages.
Species:  Rat
Technique:  Northern blotting.
References:  49
Brain (in particular glial cells).
Species:  Rat
Technique:  In situ hybridisation and immunocytochemistry.
References:  49
Spinal cord microglia
Species:  Rat
Technique:  Immunohistochemistry
References:  37
Epithelial cells lining intrahepatic bile ducts (cholangiocytes)
Species:  Rat
Technique:  RT-PCR, western blot
References:  40
Expression Datasets Click here for help

Show »

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays Click here for help
Measurement of cAMP levels in CHO cells transfected with the human P2Y12 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  29
Measurement of K+ current using patch-clamping of SCG cells transfected with the P2Y12 receptor and GIRK1 and GIRK2 channels.
Species:  Rat
Tissue:  SCG neurons.
Response measured:  Near-stable activation of GIRK.
References:  53
Measurement of Ca2+ current in SCG neurons transfected with the rat P2Y12 receptor and endogenously expressing N-type Ca2+ channels.
Species:  Rat
Tissue:  SCG neurons.
Response measured:  Inhibition of ICa(N).
References:  53
Measurement of VASP phosphorylation in human platelets endogenously expressing the P2Y12 receptor.
Species:  Human
Tissue:  Platelets.
Response measured:  Inhibition of cAMP-dependent PKA activity.
References:  5
Measurement of cAMP levels in human platelets endogenously expressing the P2Y12 receptor.
Species:  Human
Tissue:  Platelets
Response measured:  inhibition of PGE1-induced platelet cAMP accumulation
References:  9
Measurement of cAMP levels in 1321N1 cells transfected with the rat P2Y12 receptor.
Species:  Rat
Tissue:  1321N1 cells.
Response measured:  Inhibition of cAMP accumulation (PTX-sensitive).
References:  34
Measurement of GTPase activity in liposomes reconstituted with the human P2Y12 receptor and G protein α subunits
Species:  Human
Tissue:  Liposomes
Response measured:  GTPase activity
References:  7
Physiological Functions Click here for help
Role in sustaining platelet aggregation and in promoting thrombus growth and stabilization. Role in dense and alpha granule secretion, P-selectin expression and microparticle formation.
Species:  Human
Tissue:  Platelets
References:  22,33
Role in the vessel wall response to arterial injury and thrombosis
Species:  Mouse
Tissue:  Platelets
References:  18
Role in microglial chemotaxis
Species:  Mouse
Tissue:  hippocampal tissue slices
References:  25,44
Physiological Consequences of Altering Gene Expression Click here for help
P2Y12 receptor knockout mice show impaired platelet activation/adhesion in in vivo mesenteric arteries when compared to the wild-type.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  1
Microglia in P2Y12 knock-out mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  25
In spinal microglia, after partial sciatic nerve transection, antisense knockdown of P2Y12 expression suppressed the development of pain behaviors.
Species:  Rat
Tissue: 
Technique:  Antisense oligonucleotide
References:  37
Mice lacking P2Y12 displayed impaired tactile allodynia after nerve injury
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  57
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
P2ry12tm1Pcon P2ry12tm1Pcon/P2ry12tm1Pcon
involves: 129P2/OlaHsd * C57BL/6		 MGI:1918089  MP:0002551 abnormal blood coagulation PMID: 12897207 
P2ry12tm1Pcon P2ry12tm1Pcon/P2ry12tm1Pcon
involves: 129P2/OlaHsd * C57BL/6		 MGI:1918089  MP:0005464 abnormal platelet physiology PMID: 12897207 
P2ry12tm1Pcon P2ry12tm1Pcon/P2ry12tm1Pcon
involves: 129P2/OlaHsd * C57BL/6		 MGI:1918089  MP:0009549 decreased platelet aggregation PMID: 12897207 
P2ry12tm1Cjf P2ry12tm1Cjf/P2ry12tm1Cjf
involves: 129/Sv		 MGI:1918089  MP:0009549 decreased platelet aggregation PMID: 11413167 
P2ry12tm1Pcon P2ry12tm1Pcon/P2ry12tm1Pcon
involves: 129P2/OlaHsd * C57BL/6		 MGI:1918089  MP:0005606 increased bleeding time PMID: 12897207 
P2ry12tm1Cjf P2ry12tm1Cjf/P2ry12tm1Cjf
involves: 129/Sv		 MGI:1918089  MP:0005606 increased bleeding time PMID: 11413167 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Bleeding disorder, platelet-type, 8; BDPLT8
Synonyms: P2Y12 defect [Orphanet: ORPHA36355]
OMIM: 609821
Orphanet: ORPHA36355
Comments:  In a patient with congenital bleeding, heterozygosity for 2 mutations in the P2Y12 gene was found. Analysis of the patient's P2Y12 gene revealed a G-to-A transition in one allele, changing the codon for Arg-256 in the sixth transmembrane domain to Gln, and a C-to-T transition in the other allele, changing the codon for Arg-265 in the third extracellular loop to Trp. These patients generally have normal shape change responses to ADP but have impaired abilities to inhibit adenylate cyclase activity.
References:  8-9
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R112C 46
Missense Human K174E 15
Missense Human R256Q G>A 8-9
Missense Human R265W C>T 8-9
Missense Human P341A C>T 13
Single nucleotide polymorphism Human ATG to AGG in translation initiation codon 51
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  A group of single nucleotide polymorphisms in the P2Y12 gene, forming the so called P2Y12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of pheripheral arterial disease and with coronary artery disease.
References:  10,19-20,64
General Comments
Clopidogrel has a well-established role as an antithrombotic agent in the settings of percutaneous coronary intervention and acute coronary syndromes. However, it has a relatively slow onset of action and a significant number of patients show variable degrees of responsiveness or "resistance" to it. Novel P2Y12 antagonists, including Cangrelor, Prasugrel and Ticagrelor (AZD6140), all currently in phase 3 trials, have a faster onset of action, as well as more potent and less variable inhibition of platelet function [4,41]. Elinogrel (PRT060128), an investigational, direct-acting, reversible P2Y12 antagonist, is currently in phase 2 clinical studies [4]. The first report of the hP2Y12 crystal structure shows that it forms a homodimer [63]. Functional studies indicate that it can also form a heterodimer with the human P2Y1 [52] and human PAR4 [36] receptors.

References

Show »

1. Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, Koller B, Phillips DR, Conley PB. (2003) P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest, 112 (3): 398-406. [PMID:12897207]

2. Bach P, Boström J, Brickmann K, Burgess LE, Clarke D, Groneberg RD, Harvey DM, Laird ER, O'Sullivan M, Zetterberg F. (2013) 5-alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor. Future Med Chem, 5 (17): 2037-56. [PMID:24215345]

3. Baqi Y, Atzler K, Köse M, Glänzel M, Müller CE. (2009) High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors. J Med Chem, 52 (12): 3784-93. [PMID:19463000]

4. Barn K, Steinhubl SR. (2012) A brief review of the past and future of platelet P2Y12 antagonist. Coron Artery Dis, 23 (6): 368-74. [PMID:22735090]

5. Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Lafont A, Camoin L, Walter U, Eigenthaler M. (2003) Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv, 59 (3): 295-302. [PMID:12822144]

6. Bianco F, Fumagalli M, Pravettoni E, D'Ambrosi N, Volonté C, Matteoli M, Abbracchio MP, Verderio C. (2005) Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain Res Brain Res Rev, 48: 144-156. [PMID:15850653]

7. Bodor ET, Waldo GL, Hooks SB, Corbitt J, Boyer JL, Harden TK. (2003) Purification and functional reconstitution of the human P2Y12 receptor. Mol Pharmacol, 64 (5): 1210-6. [PMID:14573771]

8. Cattaneo M, Lecchi A, Randi AM, McGregor JL, Mannucci PM. (1992) Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood, 80 (11): 2787-96. [PMID:1333302]

9. Cattaneo M, Zighetti ML, Lombardi R, Martinez C, Lecchi A, Conley PB, Ware J, Ruggeri ZM. (2003) Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci USA, 100 (4): 1978-83. [PMID:12578987]

10. Cavallari U, Trabetti E, Malerba G, Biscuola M, Girelli D, Olivieri O, Martinelli N, Angiolillo DJ, Corrocher R, Pignatti PF. (2007) Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet, 8: 59. [PMID:17803810]

11. Ceruti S, Fumagalli M, Villa G, Verderio C, Abbracchio MP. (2008) Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium, 43 (6): 576-90. [PMID:18031810]

12. Chang H, Yanachkov IB, Dix EJ, Li YF, Barnard MR, Wright GE, Michelson AD, Frelinger 3rd AL. (2012) Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation. J Thromb Haemost, 10 (12): 2573-80. [PMID:23083103]

13. Cunningham MR, Nisar SP, Cooke AE, Emery ED, Mundell SJ. (2013) Differential endosomal sorting of a novel P2Y12 purinoreceptor mutant. Traffic, 14 (5): 585-98. [PMID:23387322]

14. Cusack NJ, Hourani SM. (1982) Adenosine 5-diphosphate antagonists and human platelets: no evidence that aggregation and inhibition of stimulated adenylate cyclase are mediated by different receptors. Br J Pharmacol, 76 (1): 221-7. [PMID:6282375]

15. Daly ME, Dawood BB, Lester WA, Peake IR, Rodeghiero F, Goodeve AC, Makris M, Wilde JT, Mumford AD, Watson SP et al.. (2009) Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study. Blood, 113 (17): 4110-3. [PMID:19237732]

16. Douglass JG, Patel RI, Yerxa BR, Shaver SR, Watson PS, Bednarski K, Plourde R, Redick CC, Brubaker K, Jones AC et al.. (2008) Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y12 receptor. J Med Chem, 51 (4): 1007-25. [PMID:18232657]

17. El-Tayeb A, Griessmeier KJ, Müller CE. (2005) Synthesis and preliminary evaluation of [3H]PSB-0413, a selective antagonist radioligand for platelet P2Y12 receptors. Bioorg Med Chem Lett, 15 (24): 5450-2. [PMID:16213725]

18. Evans DJ, Jackman LE, Chamberlain J, Crosdale DJ, Judge HM, Jetha K, Norman KE, Francis SE, Storey RF. (2009) Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis. Circulation, 119 (1): 116-22. [PMID:19103996]

19. Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, Gaussem P. (2003) Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation, 108 (8): 989-95. [PMID:12912815]

20. Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL. (2003) P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation, 108 (24): 2971-3. [PMID:14662702]

21. Foster HR, Fuerst E, Lee TH, Cousins DJ, Woszczek G. (2013) Characterisation of P2Y(12) receptor responsiveness to cysteinyl leukotrienes. PLoS ONE, 8 (3): e58305. [PMID:23472176]

22. Gachet C. (2008) P2 receptors, platelet function and pharmacological implications. Thromb Haemost, 99 (3): 466-72. [PMID:18327393]

23. Gretler DD, Conley PB, Andre P, Jurek M, Pandey A, Ronanko K, Leese PT, Hutchaleelaha A, Phillips DR. (2007) "First in human" experience with PRT060128, a new direct-acting, reversible, P2Y12 inhibitor for IV and oral use. J Am Coll Cardiol, 49: 326.

24. Hasegawa M, Sugidachi A, Ogawa T, Isobe T, Jakubowski JA, Asai F. (2005) Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor. Thromb Haemost, 94 (3): 593-8. [PMID:16268477]

25. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D. (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci, 9 (12): 1512-9. [PMID:17115040]

26. Herbert JM, Savi P. (2003) P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med, 3 (2): 113-22. [PMID:15199474]

27. Hoffmann K, Baqi Y, Morena MS, Glänzel M, Müller CE, von Kügelgen I. (2009) Interaction of new, very potent non-nucleotide antagonists with Arg256 of the human platelet P2Y12 receptor. J Pharmacol Exp Ther, 331 (2): 648-55. [PMID:19690189]

28. Hoffmann K, Lutz DA, Straßburger J, Baqi Y, Müller CE, von Kügelgen I. (2014) Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12 -receptor. J Thromb Haemost, 12 (11): 1898-905. [PMID:25186974]

29. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D et al.. (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature, 409 (6817): 202-7. [PMID:11196645]

30. Humphries RG, Tomlinson W, Clegg JA, Ingall AH, Kindon ND, Leff P. (1995) Pharmacological profile of the novel P2T-purinoceptor antagonist, FPL 67085 in vitro and in the anaesthetized rat in vivo. Br J Pharmacol, 115 (6): 1110-6. [PMID:7582510]

31. Humphries RG, Tomlinson W, Ingall AH, Cage PA, Leff P. (1994) FPL 66096: a novel, highly potent and selective antagonist at human platelet P2T-purinoceptors. Br J Pharmacol, 113 (3): 1057-63. [PMID:7858849]

32. Jacobson KA, Jarvis MF, Williams M. (2002) Purine and pyrimidine (P2) receptors as drug targets. J Med Chem, 45 (19): 4057-93. [PMID:12213051]

33. Kahner BN, Dorsam RT, Kunapuli SP. (2008) Role of P2Y receptor subtypes in platelet-derived microparticle generation. Front Biosci, 13: 433-9. [PMID:17981558]

34. Kauffenstein G, Hechler B, Cazenave JP, Gachet C. (2004) Adenine triphosphate nucleotides are antagonists at the P2Y receptor. J Thromb Haemost, 2 (11): 1980-8. [PMID:15550030]

35. Kennedy C, Chootip K, Mitchell C, Syed NI, Tengah A. (2013) P2X and P2Y nucleotide receptors as targets in cardiovascular disease. Future Med Chem, 5 (4): 431-49. [PMID:23495690]

36. Khan A, Li D, Ibrahim S, Smyth E, Woulfe DS. (2014) The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation. Mol Pharmacol, 86 (1): 1-11. [PMID:24723492]

37. Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K. (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci, 28 (11): 2892-902. [PMID:18337420]

38. Kong D, Xue T, Guo B, Cheng J, Liu S, Wei J, Lu Z, Liu H, Gong G, Lan T et al.. (2019) Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties. J Med Chem, 62 (6): 3088-3106. [PMID:30843696]

39. Marteau F, Le Poul E, Communi D, Communi D, Labouret C, Savi P, Boeynaems JM, Gonzalez NS. (2003) Pharmacological characterization of the human P2Y13 receptor. Mol Pharmacol, 64 (1): 104-12. [PMID:12815166]

40. Masyuk AI, Gradilone SA, Banales JM, Huang BQ, Masyuk TV, Lee SO, Splinter PL, Stroope AJ, Larusso NF. (2008) Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am J Physiol Gastrointest Liver Physiol, 295 (4): G725-34. [PMID:18687752]

41. Michelson AD. (2008) P2Y12 antagonism: promises and challenges. Arterioscler Thromb Vasc Biol, 28: s33-s38. [PMID:18174449]

42. Nonaka Y, Hiramoto T, Fujita N. (2005) Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods. Biochem Biophys Res Commun, 337: 281-288. [PMID:16185654]

43. Ohlmann P, Lecchi A, El-Tayeb A, Müller CE, Cattaneo M, Gachet C. (2013) The platelet P2Y(12) receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [(3)H]PSB-0413. Purinergic Signal, 9 (1): 59-66. [PMID:22892887]

44. Ohsawa K, Irino Y, Nakamura Y, Akazawa C, Inoue K, Kohsaka S. (2007) Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia, 55 (6): 604-16. [PMID:17299767]

45. Park HS, Hourani SM. (1999) Differential effects of adenine nucleotide analogues on shape change and aggregation induced by adnosine 5-diphosphate (ADP) in human platelets. Br J Pharmacol, 127 (6): 1359-66. [PMID:10455285]

46. Patel YM, Lordkipanidzé M, Lowe GC, Nisar SP, Garner K, Stockley J, Daly ME, Mitchell M, Watson SP, Austin SK et al.. (2014) A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J Thromb Haemost, 12 (5): 716-25. [PMID:24612435]

47. Pausch MH, Lai M, Tseng E, Paulsen J, Bates B, Kwak S. (2004) Functional expression of human and mouse P2Y12 receptors in Saccharomyces cerevisiae. Biochem Biophys Res Commun, 324 (1): 171-7. [PMID:15464998]

48. Post JM, Alexander S, Wang YX, Vincelette J, Vergona R, Kent L, Bryant J, Sullivan ME, Dole WP, Morser J et al.. (2008) Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (II): pharmacodynamic and pharmacokinetic characterization. Thromb Res, 122 (4): 533-40. [PMID:18539312]

49. Sasaki Y, Hoshi M, Akazawa C, Nakamura Y, Tsuzuki H, Inoue K, Kohsaka S. (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia, 44: 242-250. [PMID:14603465]

50. Schoenwaelder SM, Ono A, Sturgeon S, Chan SM, Mangin P, Maxwell MJ, Turnbull S, Mulchandani M, Anderson K, Kauffenstein G et al.. (2007) Identification of a unique co-operative phosphoinositide 3-kinase signaling mechanism regulating integrin alpha IIb beta 3 adhesive function in platelets. J Biol Chem, 282 (39): 28648-58. [PMID:17673465]

51. Shiraga M, Miyata S, Kato H, Kashiwagi H, Honda S, Kurata Y, Tomiyama Y, Kanakura Y. (2005) Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost, 3 (10): 2315-23. [PMID:16194207]

52. Shrestha SS, Parmar M, Kennedy C, Bushell TJ. (2010) Two-pore potassium ion channels are inhibited by both G(q/11)- and G(i)-coupled P2Y receptors. Mol Cell Neurosci, 43 (4): 363-9. [PMID:20097289]

53. Simon J, Filippov AK, Göransson S, Wong YH, Frelin C, Michel AD, Brown DA, Barnard EA. (2002) Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells. J Biol Chem, 277 (35): 31390-400. [PMID:12080041]

54. Springthorpe B, Bailey A, Barton P, Birkinshaw TN, Bonnert RV, Brown RC, Chapman D, Dixon J, Guile SD, Humphries RG et al.. (2007) From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett, 17 (21): 6013-8. [PMID:17827008]

55. Srinivasan S, Mir F, Huang JS, Khasawneh F, Lam SC, Le Breton GC. (2009) The P2Y12 antagonists, 2MeSAMP and cangrelor (ARC69931MX) can inhibit human platelet aggregation through a Gi-independent increase in cAMP levels. J Biol Chem,: -. [PMID:19346255]

56. Takasaki J, Kamohara M, Saito T, Matsumoto M, Matsumoto S, Ohishi T, Soga T, Matsushime H, Furuichi K. (2001) Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor. Mol Pharmacol, 60: 432-439. [PMID:11502873]

57. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K. (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci, 28 (19): 4949-56. [PMID:18463248]

58. Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, Erlinge D. (2004) ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol, 24 (10): 1810-5. [PMID:15308557]

59. Xiang B, Zhang G, Ren H, Sunkara M, Morris AJ, Gartner TK, Smyth SS, Li Z. (2012) The P2Y(12) antagonists, 2MeSAMP and cangrelor, inhibit platelet activation through P2Y(12)/G(i)-dependent mechanism. PLoS ONE, 7 (12): e51037. [PMID:23236426]

60. Zech G, Hessler G, Evers A, Weiss T, Florian P, Just M, Czech J, Czechtizky W, Görlitzer J, Ruf S et al.. (2012) Identification of high-affinity P2Y₁₂ antagonists based on a phenylpyrazole glutamic acid piperazine backbone. J Med Chem, 55 (20): 8615-29. [PMID:22984835]

61. Zhang FL, Luo L, Gustafson E, Lachowicz J, Smith M, Qiao X, Liu YH, Chen G, Pramanik B, Laz TM et al.. (2001) ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem, 276 (11): 8608-15. [PMID:11104774]

62. Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Müller CE et al.. (2014) Agonist-bound structure of the human P2Y12 receptor. Nature, 509 (7498): 119-22. [PMID:24784220]

63. Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W et al.. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature, 509 (7498): 115-8. [PMID:24670650]

64. Ziegler S, Schillinger M, Funk M, Felber K, Exner M, Mlekusch W, Sabeti S, Amighi J, Minar E, Brunner M et al.. (2005) Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease. Stroke, 36 (7): 1394-9. [PMID:15933261]

Contributors

Show »

How to cite this page