Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan.
FEBS Lett. 2011 Dec 15;585(24):3978-84. doi: 10.1016/j.febslet.2011.10.050. Epub 2011 Nov 10.
A(2A) adenosine receptor (A(2A)R), P2Y(1) receptor (P2Y(1)R) and P2Y(12) receptor (P2Y(12)R) are predominantly expressed on human platelets. The individual role of each of these receptors in platelet aggregation has been actively reported. Previously, hetero-oligomerization between these three receptors has been shown to occur. Here, we show that Ca(2+) signaling evoked by the P2Y(1)R agonist, 2-methylthioladenosine 5' diphosphate (2MeSADP) was significantly inhibited by the A(2A)R antagonist (ZM241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-α][1,3,5]triazin-5-yl amino]ethyl) phenol) and SCH442416) and the P2Y(12)R antagonist (ARC69931MX) (N6-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-β,γ-dichloromethylene-ATP)) using HEK293T cells expressing the three receptors. It was confirmed that inhibition of P2Y(1)R signaling by A(2A)R and P2Y(12)R antagonists was indeed mediated through A(2A)R and P2Y(12)R using 1321N1 human astrocytoma cells which do not express P2Y receptors. We expect that intermolecular signal transduction and specific conformational changes occur among components of hetero-oligomers formed by these three receptors.
A(2A) 腺苷受体 (A(2A)R)、P2Y(1) 受体 (P2Y(1)R) 和 P2Y(12) 受体 (P2Y(12)R) 主要表达于人类血小板上。这些受体中每一个在血小板聚集中的作用已被积极报道。此前，已证实这三种受体之间存在异源寡聚化。在这里，我们展示了 P2Y(1)R 激动剂 2-甲基硫代腺苷 5'二磷酸 (2MeSADP) 引发的 Ca(2+) 信号显著被 A(2A)R 拮抗剂（ZM241385（4-（2-[7-氨基-2-（2-呋喃基）[1,2,4]-三唑并[2,3-α][1,3,5]三嗪-5-基氨基]乙基）苯酚）和 SCH442416）和 P2Y(12)R 拮抗剂（ARC69931MX）（N6-（2-甲基硫代乙基）-2-（3,3,3-三氟丙基硫代）-β,γ-二氯亚甲基-ATP））抑制，该抑制作用在表达这三种受体的 HEK293T 细胞中观察到。我们通过不表达 P2Y 受体的 1321N1 人星形细胞瘤细胞证实了 A(2A)R 和 P2Y(12)R 拮抗剂对 P2Y(1)R 信号的抑制作用确实是通过 A(2A)R 和 P2Y(12)R 介导的。我们预计这些三种受体形成的异源寡聚体中的组成成分之间会发生分子间信号转导和特定构象变化。
