Department of Cardiology, Lund University, 22185 Lund, Sweden.
Cell Mol Life Sci. 2010 Feb;67(3):445-53. doi: 10.1007/s00018-009-0191-3. Epub 2009 Nov 14.
Pancreatic beta-cell loss represents a key factor in the pathogenesis of diabetes. Since the influence of purinergic signaling in beta-cell apoptosis has not been much investigated, we examined the role of the ADP receptor P2Y(13) using the pancreatic insulinoma-cell line MIN6c4 as a model system. Real time-PCR revealed high expression of the ADP receptors P2Y(1) and P2Y(13). Adding the ADP analogue, 2MeSADP, to MIN6c4 cells induced calcium influx/mobilization and inhibition of cAMP production by activation of P2Y(1) and P2Y(13), respectively. 2MeSADP reduced cell proliferation and increased Caspase-3 activity; both these effects could be fully reversed by the P2Y(13) receptor antagonist MRS2211. We further discovered that blocking the P2Y(13) receptor results in enhanced ERK1/2, Akt/PKB and CREB phosphorylation mechanisms involved in beta-cell survival. These results indicate that P2Y(13) is a proapoptotic receptor in beta-cells as the P2Y(13) receptor antagonist MRS2211 is able to protect the cells from ADP induced apoptosis.
胰岛β细胞的缺失是糖尿病发病机制的一个关键因素。由于嘌呤能信号在β细胞凋亡中的作用尚未得到充分研究，我们使用胰岛细胞瘤系 MIN6c4 作为模型系统，研究了 ADP 受体 P2Y(13)的作用。实时 PCR 显示 ADP 受体 P2Y(1)和 P2Y(13)表达水平较高。添加 ADP 类似物 2MeSADP 可分别通过激活 P2Y(1)和 P2Y(13)诱导钙内流/动员和抑制 cAMP 产生。2MeSADP 降低细胞增殖并增加 Caspase-3 活性；这两种作用均可被 P2Y(13)受体拮抗剂 MRS2211 完全逆转。我们进一步发现，阻断 P2Y(13)受体可增强参与β细胞存活的 ERK1/2、Akt/PKB 和 CREB 磷酸化机制。这些结果表明，P2Y(13)是β细胞中的促凋亡受体，因为 P2Y(13)受体拮抗剂 MRS2211 能够保护细胞免受 ADP 诱导的凋亡。
