The P2X7 receptor mediates extracellular ATP signaling implicated in the development of devastating diseases such as chronic pain and cancer. Activation of the P2X7 receptor leads to opening of the characteristic dye-permeable membrane pore for molecules up to ~900 Da. However, it remains controversial what constitutes this peculiar pore and how it opens. Here we show that the panda receptor, when purified and reconstituted into liposomes, forms an intrinsic dye-permeable pore in the absence of other cellular components. Unexpectedly, we found that this pore opens independent of its unique C-terminal domain. We also found that P2X7 channel activity is facilitated by phosphatidylglycerol and sphingomyelin, but dominantly inhibited by cholesterol through direct interactions with the transmembrane domain. In combination with cell-based functional studies, our data suggest that the P2X7 receptor itself constitutes a lipid-composition dependent dye-permeable pore, whose opening is facilitated by palmitoylated cysteines near the pore-lining helix.

中文翻译：

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P2X7 受体形成一个染料可渗透的孔，不依赖于其细胞内结构域，但依赖于膜脂成分

P2X7 受体介导的细胞外 ATP 信号与慢性疼痛和癌症等破坏性疾病的发展有关。P2X7 受体的激活导致特征性染料渗透膜孔的打开，可容纳高达 ~900 Da 的分子。然而，这个奇特的毛孔是由什么构成的以及它是如何打开的，这仍然存在争议。在这里，我们展示了熊猫受体在纯化并重组为脂质体时，在没有其他细胞成分的情况下形成了一个固有的染料可渗透孔。出乎意料的是，我们发现这个孔的打开与其独特的 C 端域无关。我们还发现 P2X7 通道活性受磷脂酰甘油和鞘磷脂促进，但通过与跨膜结构域的直接相互作用主要受胆固醇抑制。