Jin J, Tomlinson W, Kirk I P, Kim Y B, Humphries R G, Kunapuli S P
Department of Physiology, Temple University Medical School, Philadelphia, Pennsylvania, PA, USA.
Br J Pharmacol. 2001 Jun;133(4):521-8. doi: 10.1038/sj.bjp.0704114.
P2Y receptor activation in many cell types leads to phospholipase C activation and accumulation of inositol phosphates, while in blood platelets, C6-2B glioma cells, and in B10 microvascular endothelial cells a P2Y receptor subtype, which couples to inhibition of adenylyl cyclase, historically termed P2Y(AC), (P2T(AC) or P(2T) in platelets) has been identified. Recently, this receptor has been cloned and designated P2Y(12) in keeping with current P2 receptor nomenclature. Three selective P(2T) receptor antagonists, with a range of affinities, inhibited ADP-induced aggregation of washed human or rat platelets, in a concentration-dependent manner, with a rank order of antagonist potency (pIC(50), human: rat) of AR-C78511 (8.5 : 9.1)>AR-C69581 (6.2 : 6.0)>AR-C70300 (5.4 : 5.1). However, these compounds had no effect on ADP-induced platelet shape change. All three antagonists had no significant effect on the ADP-induced inositol phosphate formation in 1321N1 astrocytoma cells stably expressing the P2Y(1) receptor, when used at concentrations that inhibit platelet aggregation. These antagonists also blocked ADP-induced inhibition of adenylyl cyclase in rat platelets and C6-2B cells with identical rank orders of potency and overlapping concentration - response curves. RT - PCR and nucleotide sequence analyses revealed that the C6-2B cells express the P2Y(12) mRNA. These data demonstrate that the P2Y(AC) receptor in C6-2B cells is pharmacologically identical to the P2T(AC) receptor in rat platelets.
在许多细胞类型中，P2Y受体激活会导致磷脂酶C激活和肌醇磷酸积累，而在血小板、C6 - 2B胶质瘤细胞以及B10微血管内皮细胞中，已鉴定出一种与抑制腺苷酸环化酶偶联的P2Y受体亚型，历史上称为P2Y(AC)（血小板中为P2T(AC)或P(2T)）。最近，该受体已被克隆，并根据当前的P2受体命名法命名为P2Y(12)。三种具有不同亲和力的选择性P(2T)受体拮抗剂，以浓度依赖性方式抑制洗涤后的人或大鼠血小板的ADP诱导聚集，拮抗剂效力的等级顺序（pIC50，人：大鼠）为AR - C78511（8.5 : 9.1）> AR - C69581（6.2 : 6.0）> AR - C70300（5.4 : 5.1）。然而，这些化合物对ADP诱导的血小板形状变化没有影响。当以抑制血小板聚集的浓度使用时，所有三种拮抗剂对稳定表达P2Y(1)受体的1321N1星形细胞瘤细胞中ADP诱导的肌醇磷酸形成均无显著影响。这些拮抗剂还以相同的效力等级顺序和重叠的浓度 - 反应曲线阻断大鼠血小板和C6 - 2B细胞中ADP诱导的腺苷酸环化酶抑制。RT - PCR和核苷酸序列分析表明，C6 - 2B细胞表达P2Y(12) mRNA。这些数据表明，C6 - 2B细胞中的P2Y(AC)受体在药理学上与大鼠血小板中的P2T(AC)受体相同。
