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首页> 外文期刊>The journal of clinical investigation >The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice
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The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice

机译：P2X7受体-pannexin-1复合物降低小鼠毒蕈碱乙酰胆碱受体介导的癫痫发作敏感性

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摘要

Pannexin-1 (Panx1) plays a role in the release of ATP and glutamate in neurons and astrocytes. Panx1 can be opened at the resting membrane potential by extracellular ATP via the P2X7 receptor (P2X7R). Panx1 opening has been shown to induce neuronal death and aberrant firing, but its role in neuronal activity has not been established. Here, we report the role of the P2X7R-Panx1 complex in regulating muscarinic acetylcholine 1 (M1) receptor function. P2X7R knockout ( P2X7~(–/–) ) mice showed greater susceptibility to seizures induced by pilocarpine (PILO), an M1 receptor agonist, than their WT littermates, despite having similar levels of hippocampal M1 receptor expression. This hypersensitivity to PILO in the P2X7~(–/–) mice did not involve the GABA or glutamate system. Both administration of P2X7R antagonists and gene silencing of P2X7R or Panx1 in WT mice increased PILO-induced seizure susceptibility in a process mediated by PKC via intracellular Ca~(2+) release. Therefore, we suggest that the P2X7R-Panx1 complex may play an important role as a negative modulator of M1 receptor–mediated seizure activity in vivo.
机译：Pannexin-1（Panx1）在神经元和星形胶质细胞中ATP和谷氨酸的释放中起作用。 Panx1可以通过P2X7受体（P2X7R）通过细胞外ATP在静止膜电位处打开。 Panx1打开已显示可诱导神经元死亡和异常放电，但尚未确定其在神经元活动中的作用。在这里，我们报告P2X7R-Panx1复合体在调节毒蕈碱乙酰胆碱1（M1）受体功能中的作用。 P2X7R基因敲除小鼠（P2X7〜（– / –））与WT同窝小鼠相比，对M1受体激动剂匹罗卡品（PILO）诱发的癫痫发作表现出更大的敏感性，尽管海马M1受体的表达水平相似。 P2X7〜（– / –）小鼠对PILO的超敏反应不涉及GABA或谷氨酸系统。在WT小鼠中，P2X7R拮抗剂的施用和P2X7R或Panx1的基因沉默都增加了PILO诱导的癫痫发作易感性，该过程由PKC通过细胞内Ca〜（2+）释放介导。因此，我们建议P2X7R-Panx1复合体可能在体内作为M1受体介导的癫痫发作活动的负调节剂发挥重要作用。

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