Large pore formation uniquely associated with P2X7 purinergic receptor channels. Focus on "Are second messengers crucial for opening the pore associated with P2X7 receptor?".
Large pore formation uniquely associated with P2X7 purinergic receptor channels. Focus on "Are second messengers crucial for opening the pore associated with P2X7 receptor?".
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大孔的形成与 P2X7 嘌呤能受体通道独特相关。
DOI：
10.1152/ajpcell.00532.2004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Schwiebert,ErikM
中科院分区：
文献类型：
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作者：
Liang,Lihua;Schwiebert,ErikM
P2 X受体通道是细胞外核苷酸的受体（8，9）。相同的P2 X受体膜蛋白也形成Ca 2+可渗透的非选择性阳离子通道（8，9）。已经克隆了七种亚型（9）。它们具有相同的细胞内NH 2和COOH末端总体拓扑结构、两个跨膜α-螺旋和一个非常大的胞外结构域，占所有P2 X受体通道亚型分子量的70%（8，9）。这种拓扑结构也与哺乳动物和低等生物中的上皮Na+通道（ENaC）和ENaC亲属共享，如酸敏感离子通道、脑ENaC、线虫的简并蛋白以及果蝇的撕裂口袋和扒手基因（3，9）。在每个亚家族中的大胞外结构域内，存在偶数个保守的半胱氨酸，其被认为参与链内二硫键桥接（8）。P2 X受体是在上皮细胞和其他细胞中研究的迷人的膜蛋白。它们的大细胞外结构域暴露于不同的细胞外微环境（9，15，16）。P2 X受体通道的示意图如图1所示。据推测，P2 X质膜蛋白至少有三个功能作用的细胞。首先，它们显然是细胞外核苷酸和生物金属（如锌）的受体。其次，它们是阳离子通道，可以作为Ca 2+进入通道，引起细胞Ca 2+的持续增加。第三，由于其大的细胞外结构域，它们是ATP，锌，质子和阳离子的细胞外传感器（9）。新出现的证据表明，在这个精心设计的细胞外结构域中存在所有这些物质的结合位点（8，9）。Faria等人的研究(Ref. 5，参见本期C194页）解决了一个困扰P2 X受体生物学家一段时间的问题。多年来人们已经知道，细胞外ATP的毫摩尔浓度可以促进膜透化（9）。即使通过分子克隆出现了新的P2 X嘌呤能受体，专家们认为ATP诱导的透化受体将属于第三类嘌呤能受体分子（1）。在其克隆之前，ATP诱导的透化受体被称为P2 Z受体，以将其与P2 X受体通道和P2 Y G蛋白偶联的嘌呤能受体区分开来（1）。然而，Surprenant et al. (13)克隆了与P2 X1 -6具有显著同源性的第七个P2 X受体通道基因。它被归类为P2 X7，并显示出在表达它的细胞上赋予两种表型。首先，观察到具有确定单通道电导的Ca 2+渗透性非选择性阳离子通道，其表型与P2 X1 -6一致（13）。P2 X6被认为是一个无声通道，尽管最近的一项研究表明这可能不是真的（6）。然而，表达P2 X7的细胞还表达了更大的膜孔，其可渗透1，000 Da的大化合物和染料（13）。这些染料的摄取用于测量P2 X7功能以及细胞凋亡的状态。P2 X7和细胞凋亡密切相关;然而，尚不清楚细胞凋亡是否诱导P2 X7表达（即，P2 X7是细胞凋亡的标志物）或P2 X7是否是驱动细胞进入程序性细胞死亡所必需的（8，13）。North（8）在最近对P2 X受体分子生理学的综合综述中，总结了P2 X7介导的孔形成、染料摄取和细胞凋亡。其他最近的论文（4，7，11，12，14），除了文章的重点由法里亚等人。(5)，解决了这些问题。图1显示了P2 X7与P2 X1 -6不同的分子特征。它...
P2X RECEPTOR CHANNELS ARE RECEPTORS for extracellular nucleotides (8, 9). The same P2X receptor membrane protein also forms a Ca2+-permeable, nonselective cation channel (8, 9). Seven subtypes have been cloned (9). They share the same overall topology of intracellular NH2 and COOH termini, two transmembrane α-helices, and a very large extracellular domain that accounts for 70% of the molecular mass in all P2X receptor channel subtypes (8, 9). This topology is also shared with the epithelial Na+ channel (ENaC) and ENaC relatives in mammals and in lower organisms such as the acid-sensing ion channels, brain ENaCs, degenerins of the nematode, and ripped pocket and pickpocket genes of Drosophila (3, 9). Within the large extracellular domain in each subfamily, there is an even number of conserved cysteines that are thought to participate in intrachain disulfide bridging (8). P2X receptors are fascinating membrane proteins to study in epithelial and other cells. Their large extracellular domains are exposed to diverse extracellular microenvironments (9, 15, 16). A schema of a P2X receptor channel is shown in Fig. 1. It is hypothesized that P2X plasma membrane proteins serve at least three functional roles for a cell. First, they are clearly receptors for extracellular nucleotides and for biometals such as zinc. Second, they are cation channels that can serve as Ca2+ entry channels to elicit a sustained increase in cellular Ca2+. Third, by virtue of their large extracellular domain, they are extracellular sensors for ATP, zinc, protons, and cations (9). Emerging evidence suggests that there are binding sites for all of these substances within this elaborate extracellular domain (8, 9). The study by Faria et al.(Ref. 5, see p. C194 in this issue) tackles a problem that has confounded P2X receptor biologists for some time. It has been known for many years that millimolar concentrations of extracellular ATP can promote membrane permeabilization (9). Even as the new class of P2X purinergic receptors was emerging through molecular cloning, experts thought that the ATP-induced permeabilization receptor would fall into a third molecular class of purinergic receptors (1). Before its cloning, the ATP-induced permeabilization receptor was referred to as the P2Z receptor to distinguish it from P2X receptor channels and P2Y G protein-coupled purinergic receptors (1). However, Surprenant et al.(13) cloned a seventh P2X receptor channel gene that had significant homology with P2X1–6. It was classified as P2X7 and was shown to confer two phenotypes on a cell in which it was expressed. First, a Ca2+-permeable, nonselective cation channel of a defined single-channel conductance was observed, a phenotype consistent with P2X1–6 (13). P2X6 was thought to be a silent channel, although a recent study suggested that this may not be true (6). However, the P2X7-expressing cell also expressed a larger membrane pore that was permeable to large compounds and dyes that were 1,000 Da (13). Uptake of such dyes is used to measure P2X7 function as well as the state of apoptosis. P2X7 and apoptosis are closely linked; however, it is not clear whether apoptosis induces P2X7 expression (ie, P2X7 is a marker of apoptosis) or whether P2X7 is essential to drive a cell into programmed cell death (8, 13). North (8), in a recent comprehensive review of the molecular physiology of P2X receptors, summarized P2X7-mediated pore formation, dye uptake, and apoptosis. Other recent papers (4, 7, 11, 12, 14), in addition to the article in focus by Faria et al.(5), have addressed these issues. Figure 1 shows a molecular feature of P2X7 that sets it apart from P2X1–6. It …