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 P2X7 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.

P2X7受体介导细胞外ATP信号传导，涉及破坏性疾病的发展，例如慢性疼痛和癌症。P2X7受体的激活导致特征性的染料可渗透膜孔打开，最大可达900 Da。然而，仍然有争议的是什么构成了这个特殊的毛孔以及它是如何打开的。在这里我们显示，当熊猫P2X7受体纯化并重构为脂质体时，在没有其他细胞成分的情况下形成了固有的染料可渗透性孔。出乎意料的是，我们发现该孔独立于其独特的C末端域开放。我们还发现，磷脂酰甘油和鞘磷脂促进了P2X7通道的活性，但是通过与跨膜结构域的直接相互作用，胆固醇显着地抑制了P2X7通道的活性。