Structural insights into the function of P2X4: an ATP-gated cation channel of neuroendocrine cells.
Structural insights into the function of P2X4: an ATP-gated cation channel of neuroendocrine cells.
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DOI：
10.1007/s10571-010-9568-y
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发表时间：
2010-11
影响因子：
4
通讯作者：
Zemkova, Hana
中科院分区：
文献类型：
--
作者：
Stojilkovic, Stanko S.;Yan, Zonghe;Obsil, Tomas;Zemkova, Hana
关键词：
P2 X4受体（P2 X4 R）是ATP门控阳离子通道家族的成员，由三个亚基组成。每个亚基具有两个跨膜（TM）结构域，其通过大的细胞外环和位于细胞内的N-和C-末端连接。这些受体在可兴奋和不可兴奋的细胞中表达，并且已经涉及膜兴奋性、钙信号传导、神经递质和激素释放以及疼痛生理学的调节。P2 X4 R在激动剂应用的几秒钟内迅速激活和脱敏，两者的速率都依赖于ATP浓度，并且迅速失活且与ATP浓度无关。破坏保守的半胱氨酸胞外域残基影响ATP结合和门控。P2 X4 R的几个胞外域残基被鉴定为对ATP结合至关重要，包括K67、K313和R295。胞外结构域残基也负责P2 X4 R的变构调节; H140负责铜结合，H286用质子调节受体功能。伊维菌素敏化受体，放大电流幅度，并通过在TM区域结合减缓受体失活。扫描突变的TM揭示了螺旋拓扑结构的两个域，并建议，受体功能是严重依赖于保守的Y 42残基。在这篇简短的文章中，我们总结了这项研究，并使用基于斑马鱼P2X4.1受体结晶的模型重新解释它。
The P2X4 receptor (P2X4R) is a member of a family of ATP-gated cation channels that are composed of three subunits. Each subunit has two transmembrane (TM) domains linked by a large extracellular loop and intracellularly located N- and C-termini. The receptors are expressed in excitable and non-excitable cells and have been implicated in the modulation of membrane excitability, calcium signaling, neurotransmitter and hormone release, and pain physiology. P2X4Rs activate rapidly and desensitize within the seconds of agonist application, both with the rates dependent on ATP concentrations, and deactivate rapidly and independently of ATP concentration. Disruption of conserved cysteine ectodomain residues affects ATP binding and gating. Several ectodomain residues of P2X4R were identified as critical for ATP binding, including K67, K313, and R295. Ectodomain residues also account for the allosteric regulation of P2X4R; H140 is responsible for copper binding and H286 regulates receptor functions with protons. Ivermectin sensitized receptors, amplified the current amplitude, and slowed receptor deactivation by binding in the TM region. Scanning mutagenesis of TMs revealed the helical topology of both domains, and suggested that receptor function is critically dependent on the conserved Y42 residue. In this brief article, we summarize this study and re-interpret it using a model based on crystallization of the zebrafish P2X4.1 receptor.
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