P2Y12

P2Y12 is a chemoreceptor for adenosine diphosphate (ADP)[5][6] that belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors.[7] This P2Y receptor family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. The P2Y12 receptor is involved in platelet aggregation and is thus a biological target for the treatment of thromboembolisms and other clotting disorders. Two transcript variants encoding the same isoform have been identified for this gene.[8]

P2RY12
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesP2RY12, ADPG-R, BDPLT8, HORK3, P2T(AC), P2Y(12)R, P2Y(AC), P2Y(ADP), P2Y(cyc), P2Y12, SP1999, purinergic receptor P2Y12
External IDsOMIM: 600515 MGI: 1918089 HomoloGene: 11260 GeneCards: P2RY12
Gene location (Human)
Chr.Chromosome 3 (human)[1]
Band3q25.1Start151,337,380 bp[1]
End151,384,812 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

64805

70839

Ensembl

ENSG00000169313

ENSMUSG00000036353

UniProt

Q9H244

Q9CPV9

RefSeq (mRNA)

NM_176876
NM_022788

NM_027571
NM_001357007
NM_001357008
NM_001357010

RefSeq (protein)

NP_073625
NP_795345

NP_081847
NP_001343936
NP_001343937
NP_001343939

Location (UCSC)Chr 3: 151.34 – 151.38 MbChr 3: 59.22 – 59.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In the field of purinergic signaling, the P2Y12 protein on the periphery is found mainly but not exclusively on the surface of blood platelets, and is an important regulator in blood clotting.[9] In the central nervous system, this receptor has been found primarly expressed on microglia, where it is necessary for physiological and pathological microglial actions, such as monitoring neuronal functions and microglial neuroprotection.[10]. Recent evidence show that the P2Y12 receptor is also expressed in oligodendrocytes where it might be involved in the migration and adhesion of the glial processes to axons to be myelinated. [11]

P2Y12 inhibitors

The drugs clopidogrel (Plavix), prasugrel (Efient, Effient), ticagrelor (Brilinta), and cangrelor (Kengreal) bind to this receptor and are marketed as antiplatelet agents.[5]

For acute coronary syndrome

The combination of P2Y12 inhibitors and aspirin, which called dual antiplatelet treatment, remains the first line treatment of acute coronary syndromes. Recent suggested prasugrel is superior than ticagrelor.[12]

Antiplatelet treatment of STEMI

In patients undergoing primary PCI for an ST-segment elevation myocardial infarction (STEMI), US,[13] European,[14] and Canadian[15] guidelines recommend that a P2Y12 inhibitor should be administered as soon as possible, although it is unclear whether administration of these medications before the patient arrives at the hospital confers additional benefits compared with in-hospital administration.[15]

On the other hand, P2Y12 inhibitors do not change the risk of death when given as a pretreatment prior to routine percutaneous coronary intervention (PCI) in people who have had a non-ST-elevation myocardial infarction (NSTEMI). Though, a P2Y12 inhibitor in addition to aspirin should be administered for up to 12 months to most patients with non-ST-elevation acute coronary syndrome. They do however increase the risk of bleeding and decrease the risk of further cardiovascular problems. Thus their routine use in this context is of questionable value.[16]

A network meta-analysis of 37 studies involving 88,402 STEMI patients and 5,077 major adverse cardiac events (MACE) patients found that use of prasugrel was associated with lower mortality and MACE than other drugs in this class (clopidogrel and ticagrelor).[17]

References
  1. GRCh38: Ensembl release 89: ENSG00000169313 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000036353 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (Jan 2001). "Identification of the platelet ADP receptor targeted by antithrombotic drugs". Nature. 409 (6817): 202–7. Bibcode:2001Natur.409..202H. doi:10.1038/35051599. PMID 11196645.
  6. Nicholas RA (Sep 2001). "Identification of the P2Y(12) receptor: a novel member of the P2Y family of receptors activated by extracellular nucleotides". Molecular Pharmacology. 60 (3): 416–20. PMID 11502870.
  7. Murugappa S, Kunapuli SP (2006). "The role of ADP receptors in platelet function". Frontiers in Bioscience. 11 (1): 1977–86. doi:10.2741/1939. PMID 16368572.
  8. "Entrez Gene: P2RY12 purinergic receptor P2Y, G-protein coupled, 12".
  9. Dorsam RT, Kunapuli SP (Feb 2004). "Central role of the P2Y12 receptor in platelet activation". The Journal of Clinical Investigation. 113 (3): 340–5. doi:10.1172/JCI20986. PMC 324551. PMID 14755328.
  10. Cserép et al., Science 12 Dec 2019:eaax6752 DOI:10.1126/science.aax6752 https://science.sciencemag.org/content/early/2019/12/11/science.aax6752
  11. Amadio, S. et al, Neuroscience 1 Sept 2006 DOI: 10.1007/s11302-011-9283-2 https://www.ncbi.nlm.nih.gov/pubmed/16831517
  12. Schüpke, Stefanie; Neumann, Franz-Josef; Menichelli, Maurizio; Mayer, Katharina; Bernlochner, Isabell; Wöhrle, Jochen; Richardt, Gert; Liebetrau, Christoph; Witzenbichler, Bernhard; Antoniucci, David; Akin, Ibrahim (2019-10-17). "Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes". New England Journal of Medicine. 381 (16): 1524–1534. doi:10.1056/NEJMoa1908973. ISSN 0028-4793. PMID 31475799.
  13. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW, et al. (American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines) (January 29, 2013). "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. 127 (4): e362-425. doi:10.1161/CIR.0b013e3182742cf6. PMID 23247304.
  14. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, et al. (ESC Scientific Document Group) (January 7, 2018). "2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)". Eur Heart J. 39 (2): 119–177. doi:10.1093/eurheartj/ehx393. PMID 28886621.
  15. Wong GC, Welsford M, Ainsworth C, Abuzeid W, Fordyce CB, Greene J, Huynh T, Lambert L, Le May M, Lutchmedial S, Mehta SR, Natarajan M, Norris CM, Overgaard CB, Perry Arnesen M, Quraishi A, Tanguay JF, Traboulsi M, van Diepen S, Welsh R, Wood DA, Cantor WJ, et al. (members of the Secondary Panel) (February 2019). "2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST-Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion". Can J Cardiol. 35 (2): 107–132. doi:10.1016/j.cjca.2018.11.031. PMID 30760415.
  16. Bellemain-Appaix A, Kerneis M, O'Connor SA, Silvain J, Cucherat M, Beygui F, Barthélémy O, Collet JP, Jacq L, Bernasconi F, Montalescot G (2014). "Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis". BMJ. 349 (aug 06 2): g6269. doi:10.1136/bmj.g6269. PMC 4208629. PMID 25954988.
  17. Rafique AM, Nayyar P, Wang TY, Mehran R, Baber U, Berger PB, Tobis J, Currier J, Dave RH, Henry TD (May 2016). "Optimal P2Y12 Inhibitor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Network Meta-Analysis". JACC Cardiovasc Interv. 9 (10): 1036–46. doi:10.1016/j.jcin.2016.02.013. PMID 27198684.


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