Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors
Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors
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DOI：
10.1111/j.1476-5381.2009.00233.x
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发表时间：
2009-08-01
影响因子：
7.3
通讯作者：
Jarvis, Michael F.
中科院分区：
文献类型：
--
作者：
Donnelly-Roberts, Diana L.;Namovic, Marian T.;Jarvis, Michael F.
背景与目的：P2X7受体的急性激活迅速打开非选择性阳离子通道。持续的 P2X7 受体激活导致溶细胞孔的形成，这是由下游半通道募集到细胞表面介导的。据报道，物种和单核苷酸多态性介导的 P2X7 受体激活差异使对 P2X7 受体生理作用的理解变得复杂。进行研究以确定人、大鼠和小鼠 P2X7 受体之间的药理学差异。实验方法：比较重组小鼠、大鼠和人 P2X7 受体之间受体介导的钙流入和 Yo-Pro 摄取变化。对于小鼠 P2X7 受体，还比较了野生型 (BALB/c) 和报道的功能丧失 (C57BL/6) P2X7 受体。 主要结果：BzATP [2,3-O-(4-苯甲酰基苯甲酰基)-ATP] 在刺激大鼠、人类、BALB/c 和 C57BL/6 小鼠的钙流入和 Yo-Pro 摄取方面比 ATP 更有效 P2X7 受体。两种选择性 P2X7 受体拮抗剂 A-740003 和 A-438079 可有效阻断哺乳动物物种的 P2X7 受体激活。一些报道的 P2X1 受体拮抗剂 [例如MRS 2159（4-[（4-甲酰基-5-羟基-6-甲基-3-[（膦酰氧基）甲基}-2-吡啶基）偶氮]-苯甲酸）、PPNDS 和 NF279] 阻断 P2X7 受体。 NF279 完全阻断人类 P2X7 受体，但仅部分阻断 BALB/c P2X7 受体，并且对 C57BL/6 P2X7 受体无活性。 结论和意义：这些数据为跨哺乳动物物种的 P2X7 受体拮抗剂药理学提供了新的见解。广泛使用的基因敲除背景小鼠品系 (C57BL/6) 中的 P2X7 受体药理学与野生型小鼠 P2X7 受体相似。与早期的非选择性拮抗剂相比，几种结构新颖、选择性和竞争性的 P2X7 受体拮抗剂表现出较小的物种差异。
Background and purpose:Acute activation of P2X7 receptors rapidly opens a non-selective cation channel. Sustained P2X7 receptor activation leads to the formation of cytolytic pores, mediated by downstream recruitment of hemichannels to the cell surface. Species- and single-nucleotide polymorphism-mediated differences in P2X7 receptor activation have been reported that complicate understanding of the physiological role of P2X7 receptors. Studies were conducted to determine pharmacological differences between human, rat and mouse P2X7 receptors.Experimental approach:Receptor-mediated changes in calcium influx and Yo-Pro uptake were compared between recombinant mouse, rat and human P2X7 receptors. For mouse P2X7 receptors, wild-type (BALB/c) and a reported loss of function (C57BL/6) P2X7 receptor were also compared.Key results:BzATP [2,3-O-(4-benzoylbenzoyl)-ATP] was more potent than ATP in stimulating calcium influx and Yo-Pro uptake at rat, human, BALB/c and C57BL/6 mouse P2X7 receptors. Two selective P2X7 receptor antagonists, A-740003 and A-438079, potently blocked P2X7 receptor activation across mammalian species. Several reported P2X1 receptor antagonists [e.g. MRS 2159 (4-[(4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl}-2-pyridinyl)azo]-benzoic acid), PPNDS and NF279] blocked P2X7 receptors. NF279 fully blocked human P2X7 receptors, but only partially blocked BALB/c P2X7 receptors and was inactive at C57BL/6 P2X7 receptors.Conclusions and implications:These data provide new insights into P2X7 receptor antagonist pharmacology across mammalian species. P2X7 receptor pharmacology in a widely used knockout background mouse strain (C57BL/6) was similar to wild-type mouse P2X7 receptors. Several structurally novel, selective and competitive P2X7 receptor antagonists show less species differences compared with earlier non-selective antagonists.