P2Y12 receptor [previously known as SP1999, P2T(AC), and P2Y(AC)] 2.1:NUCT:6:P2Y12
| TM | aa | AC | Chr. Map | References | |
|---|---|---|---|---|---|
| Human | 7 | 342 | NM_022788*; NM_176876 | 3q24—25 | Hollopeter et al. (2001) |
| Rat | 7 | 347 | NM_022800 | 2q31 | Hollopeter et al. (2001) |
| Mouse | 7 | 343 | NM_027571 | 2 | |
| Functional assays | cAMP measurement in CHO cells and CHO cells stably transfected with hP2Y12 (Hollopeter et al., 2001; Zhang et al., 2001); FLIPR assay in CHO-dihydrofolate reductase-deficient transiently or stably transfected with hP2Y12 (Zhang et al., 2001); cAMP measurement in platelets (Cattaneo et al., 2003) | ||||
| Ligand | Action | Selectivity | Endogenous | References |
|---|---|---|---|---|
| ATP** | Partial agonist | No | Yes | Waldo and Harden (2004) |
| 2-MeSADP | Agonist | No | No | Zhang et al. (2001) |
| 2-MeSATP | Agonist | No | No | Zhang et al. (2001) |
| ADP | Agonist | No | Yes | Zhang et al. (2001) |
| ADPβS | Agonist | No | No | Zhang et al. (2001) |
| ATPγS | Agonist | No | No | Zhang et al. (2001) |
| 2ClATP | Agonist | No | No | Zhang et al. (2001) |
| Reactive blue 2 | Antagonist | No | No | Zhang et al. (2001) |
| Suramin | Antagonist | No | No | Zhang et al. (2001) |
| Ticlopidine | Antagonist | No | No | Savi and Herbert (2005) |
| Clopidogrel | Antagonist | No | No | Savi and Herbert (2005) |
| CS-747 | Antagonist | No | No | Savi and Herbert (2005) |
| AR-C66096MX | Antagonist | No | No | Gachet (2005) |
| AR-M69931MX | Antagonist | No | No | Gachet (2005) |
| AR-C67085MX | Antagonist | No | No | Gachet (2005) |
| Agonist potencies | cAMP assays: 2-MeSATP (EC50 3.4 ± 0.5 nM) = 2-MeSADP (EC50 14.1 ± 2 nM) > ADP (EC50 60.7 ± 10 nM) > ATPγS (EC50 110 ± 100 nM) > ADPβS (EC50 191 ± 20 nM) > 2ClATP (EC50 636 ± 100 nM) (Zhang et al., 2001); FLIPR assay: 2-MeSADP (EC50 2.3 ± 0.3 nM) = 2-MeSATP (EC50 3.4 ± 0.3 nM) > ADP (EC50 74 ± 10 nM) = ADPβS (EC50 89 ± 15 nM) > 2ClATP (EC50 470 ± 100 nM) > ATPγS (EC50 1200 ± 200 nM) (Zhang et al., 2001) | |||
| Antagonist potencies | Reactive blue 2 (Ki = 1.3 μM), suramin (Ki = 3.6 μM); AR-C66096, AR-C69931MX, tioclopidine, clopidogrel [prodrug that produces a metabolite that irreversibly binds to P2Y12 (Savi et al., 2000; Gachet et al., 2001, 2005)]; no effect of PPADS | |||
| Radioligand assays | Binding of [33P]2-MeSADP (Cattaneo et al., 1997) | |||
| Radioligands | [33P]2-MeSADP (Cattaneo et al., 1997) | |||
| Transduction mechanism | Gαi, inhibition of adenylate cyclase | |||
| Distribution | Brain (in particular glial cells), spinal cord, platelets (Zhang et al., 2001; Sasaki et al., 2003) | |||
| Tissue function | Role in dense granule secretion (Daniel et al., 1998), fibrinogen-receptor activation, and thrombus formation (Gachet, 2005); role in the recruitment of the platelets to the site of injury and in the enhancement of the efficiency of platelet activation by other agonists, such as thrombin and thromboxane A2 (Gachet, 2005); this receptor is defective in several patients with blood coagulation disorders (Cattaneo et al., 2000, 2003; Hollopeter et al., 2001) | |||
| Phenotypes | P2Y12-null mice*** | |||
| Comments | Two transcript variants that encode the same isoform have been identified for this gene*; ATP is a partial agonist**; when P2Y12 expression is low, as is seen in platelets, it acts as an antagonist, whereas at high expression levels, as seen with recombinant receptors, it is an agonist (Waldo and Harden, 2004); radiation hybrid analysis mapped the P2Y12 gene on 3q24—3q25 (Hollopeter et al., 2001), a region that also includes the P2Y1, P2Y13, and P2Y14 receptors; in a patient with congenital bleeding, Cattaneo et al. (2003) found compound heterozygosity for two mutations in the P2Y12 gene: neither mutation interfered with receptor surface expression but both altered function—in particular, these patients generally have normal platelet shape change responses to ADP but have impaired abilities to inhibit adenylate cyclase activity (Cattaneo et al., 1992); P2Y12 knockout mice seem normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen (André et al., 2003)***; clinical studies using clopidogrel demonstrate a significantly reduced risk of peripheral artery disease, myocardial infarction, ischemic stroke, or vascular death compared with aspirin therapy; phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation with a half-life of only a few minutes (Gachet, 2005) | |||
aa, amino acids; AC, accession; chr., chromosome; FLIPR, fluorometric imaging plate reader.