The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor
The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor
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DOI：
10.1016/j.neuropharm.2013.07.027
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发表时间：
2013-12-01
影响因子：
4.7
通讯作者：
Schaefer, Michael
中科院分区：
文献类型：
--
作者：
Hempel, Christoph;Noerenberg, Wolfgang;Schaefer, Michael
P2 X7是一种ATP门控阳离子通道，参与免疫细胞激活、痛觉过敏和神经病理性疼痛。通过调节大脑中细胞因子的释放，P2 X7与情绪障碍和精神分裂症的病理生理学有关。我们在这里评估了123种作用于中枢神经系统的药物对人类P2 X7的影响。最突出的是，三环类抗精神病药丙氯拉嗪（PCP）和三氟拉嗪（TFP）强效抑制P2 X7介导的Ca 2+内流，染料渗透和离子电流。在二价阳离子浴解决方案或长时间孵育后，ATP诱发的P2 X7电流被抑制10 μ M PCP。这种作用与多巴胺受体拮抗作用无关。令人惊讶的是，五氯苯酚与ATP共同应用增强了低二价阳离子浓度浴溶液中的内向电流。细胞内灌注PCP没有取代细胞外应用的药物，表明其结合位点可从细胞外空间。由于PCP对P2 X7电流的增强作用是电压依赖性的，因此至少有一个位点可能位于膜的电场内。当PCP改变通道开放和关闭动力学时，ATP的表观亲和力保持不变（增强）或略有变化（抑制）。在人单核细胞衍生的巨噬细胞中的测量证实了PCP诱导的ATP诱发的Ca 2+内流、Yo-Pro-1渗透性和全细胞电流的抑制。有趣的是，在大鼠星形胶质细胞培养物或小鼠骨髓衍生的巨噬细胞中，异源表达的大鼠或小鼠P2 X7或天然P2 X7均不被具有类似效力的哌嗪抑制。我们得出结论，哌嗪类神经抑制剂是有效的，但物种选择性变构调节剂的人，但不是小鼠P2 X7受体。(C)2013爱思唯尔有限公司保留所有权利。
P2X7, an ATP-gated cation channel, is involved in immune cell activation, hyperalgesia and neuropathic pain. By regulating cytokine release in the brain, P2X7 has been linked to the pathophysiology of mood disorders and schizophrenia. We here assess the impact of 123 drugs that act in the central nervous system on human P2X7. Most prominently, the tricyclic antipsychotics prochlorperazine (PCP) and trifluoperazine (TFP) potently inhibited P2X7-mediated Ca2+ entry, dye permeation and ionic currents. In divalent cation-containing bath solutions or after prolonged incubation, ATP-evoked P2X7 currents were inhibited by 10 mu M PCP. This effect was not related to dopamine receptor antagonism. Surprisingly, PCP co-applied with ATP enhanced inward currents in bath solutions with low divalent cation concentrations. Intracellular perfusion with PCP did not substitute for the extracellularly applied drug, indicating that its binding sites are accessible from the extracellular space. Since P2X7 current potentiation by PCP was voltage-dependent, at least one site may be located within the electrical field of the membrane. While the channel opening and closure kinetic was altered by PCP, the apparent affinity of ATP remained unchanged (potentiation) or changed slightly (inhibition). Measurements in human monocyte-derived macrophages confirmed the PCP-induced inhibition of ATP-evoked Ca2+ influx, Yo-Pro-1 permeability, and whole cell currents. Interestingly, neither heterologously expressed rat or mouse P2X7 nor native P2X7 in rat astrocyte cultures or in mouse bone marrow-derived macrophages were inhibited by per-azines with a similar potency. We conclude that perazine-type neuroleptics are potent, but species-selective allosteric modulators of human but not murine P2X7 receptors. (C) 2013 Elsevier Ltd. All rights reserved.