PDF(Pubmed)
Abstract：
P2X7 is a member of the Ionotropic Purinergic Receptor (P2X) family. The P2X family of receptors is composed of seven (P2X1-7), ligand-gated, nonselective cation channels. Changes in P2X expression have been reported in multiple disease models. P2Xs have large complex extracellular domains that function as receptors for a variety of ligands, including endogenous and synthetic agonists and antagonists. ATP is the canonical agonist. ATP affinity ranges from nanomolar to micromolar for most P2XRs, but P2X7 has uniquely poor ATP affinity. In many physiological settings, it may be difficult to achieve the millimolar extracellular ATP concentrations needed for P2X7 channel activation; however, channel function is implicated in pain sensation, immune cell function, cardiovascular disease, cancer, and osteoporosis. Multiple high-resolution P2X7 structures have been solved in apo-, ATP-, and antagonist-bound states. P2X7 structural data reveal distinct allosteric and orthosteric antagonist-binding sites. Both allosteric and orthosteric P2X7 antagonists are well documented to inhibit ATP-evoked channel current. However, a growing body of evidence supports P2X7 activation by non-nucleotide agonists, including extracellular histone proteins and human cathelicidin-derived peptides (LL-37). Interestingly, P2X7 non-nucleotide agonism is not inhibited by allosteric antagonists, but is inhibited by orthosteric antagonists. Herein, we review P2X7 function with a focus on the efficacy of available pharmacology on P2X7 channel current activation by non-nucleotide agonists in effort to understand agonist/antagonist efficacy, and consider the impact of these data on the current understanding of P2X7 in physiology and disease given these limitations of P2X7-selective antagonists and incomplete knockout mouse models.
摘要：
P2X7是离子型嘌呤能受体(P2X)家族的成员。P2X家族的受体由七个（P2X1-7）组成，配体门控，非选择性阳离子通道。在多种疾病模型中已经报道了P2X表达的变化。P2X具有大型复杂的胞外域，可作为各种配体的受体，包括内源性和合成的激动剂和拮抗剂。ATP是典型的激动剂。对于大多数P2XRs，ATP亲和力范围从纳摩尔到微摩尔，但P2X7具有独特的低ATP亲和力。在许多生理环境中，可能难以实现P2X7通道激活所需的毫摩尔细胞外ATP浓度;然而,通道功能与痛觉有关，免疫细胞功能，心血管疾病,癌症,和骨质疏松症。多个高分辨率P2X7结构已经在apo-,ATP-,和拮抗剂束缚状态。P2X7结构数据揭示了不同的变构和正构拮抗剂结合位点。已充分证明，变构和正构P2X7拮抗剂均能抑制ATP诱发的通道电流。然而,越来越多的证据支持非核苷酸激动剂激活P2X7，包括细胞外组蛋白和人导管素衍生肽(LL-37)。有趣的是,P2X7非核苷酸激动不受变构拮抗剂的抑制，但被正构拮抗剂抑制。在这里，我们回顾了P2X7功能，重点是非核苷酸激动剂对P2X7通道电流激活的现有药理学功效，以了解激动剂/拮抗剂的功效。考虑到P2X7选择性拮抗剂和不完全基因敲除小鼠模型的这些局限性，并考虑这些数据对目前对P2X7在生理学和疾病中的理解的影响。
