Annotated PGx Gene Information for P2RY12
Submitted by: Katrin Sangkuhl (PharmGKB)
Reviewed by: under review
Submitted date: Feb 28, 2008
| Gene HGNC Name: | P2RY12 |
|---|---|
| Gene Common Name: | purinergic receptor P2Y, G-protein coupled, 12 |
| Introductory Information: | The product of this gene belongs to the G-protein coupled receptor family. Eight different mammalian P2Y (P2Y1, 2, 4, 6, 11-14) receptor subtypes have been cloned and characterized so far. P2RY1, 11, 12, and 13 are activated by adenosine nucleotides [15955565]. P2RY12 is selectively expressed in human platelets and, also shows lower expression in brain (glia cells) [11196645]. Platelet activation by ADP plays a crucial role in haemostasis and thrombosis. The coactivation of P2YR1 and P2RY12 is necessary for full platelet aggregation in response to ADP. The P2RY12 couples via the inhibitory G alpha protein subunit resulting in the inhibition of cAMP production, and therefore a subsequent reduction in intracellular cAMP content. Furthermore, P2RY12 receptor induces platelet aggregation through a weak activation of glycoprotein IIb/IIIa integrin via PI3-kinase pathway [12912815]. Numerous studies established the key role of this receptor for the ADP-dependent amplification of platelet aggregation induced by other agonists such as thomboxane A2 and thrombin [16611109] [17115040]. The P2RY12 gene is located in the q25.1 region of chromosome 3. It contains three exons and the last exon encodes the entire 342-amino acid protein [18175333]. Two transcript variants encoding the same isoform have been identified for this gene. Inactivating mutations in P2RY12 cause a congenital bleeding disorder [609821]. Because of its role in the formation and stabilization of a thrombus, the P2RY12 is a target of antithrombotic drugs like ticlopidine or clopidogrel [15955565]. These agents have to be metabolized in the liver to generate active metabolites; this results in a delay in action of these compounds. An alternative to these irreversible agents could be the use of competitive P2RY12 antagonists with no delay in action on the receptor, benefiting mainly acute situations such as myocardial infarction [15955565]. Competitive P2RY12 antagonists have been shown to be effective in experimental thrombosis as well as in several clinical trials [PMID:15955565, 12411949, 12913786, 14668029, 14755328, 15852221, 15852223, 12588753]. |
| Key PubMed IDs: | 16611109, 15955565, 12913786, 14668029, 14755328 |
| Key Pathways: | Platelet Aggregation Pathway, Antiplatelet Drug Clopidogrel Pathway |
| Drugs/Substrates: | clopidogrel, ticlopidine |
| Phenotypes/Diseases: | Cardiovascular Diseases, congenital bleeding disorder |
| Important Variants: | P2RY12:744T>C |
| Important Haplotypes: | P2RY12:H2 haplotype |