Paukert Martin, Chen Xuanmao, Polleichtner Georg, Schindelin Hermann, Gründer Stefan
Department of Physiology II, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany.
Department of Physiology II, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany; Department of Physiology II, University of Würzburg, Röntgenring 9, 97070 Würzburg, Germany.
J Biol Chem. 2008 Jan 4;283(1):572-581. doi: 10.1074/jbc.M706811200. Epub 2007 Nov 1.
Acid-sensing ion channels are ligand-gated cation channels, gated by extracellular H(+). H(+) is the simplest ligand possible, and whereas for larger ligands that gate ion channels complex binding sites in the three-dimensional structure of the proteins have to be assumed, H(+) could in principle gate a channel by titration of a single amino acid. Experimental evidence suggests a more complex situation, however. For example, it has been shown that extracellular Ca(2+) ions compete with H(+); probably Ca(2+) ions bound to the extracellular loop of ASICs stabilize the closed state of the channel and have to be displaced before the channel can open. In such a scheme, amino acids contributing to Ca(2+) binding would also be candidates contributing to H(+) gating. In this study we systematically screened more than 40 conserved, charged amino acids in the extracellular region of ASIC1a for a possible contribution to H(+) gating. We identified four amino acids where substitution strongly affects H(+) gating: Glu(63), His(72)/His(73), and Asp(78). These amino acids are highly conserved among H(+)-sensitive ASICs and are candidates for the "H(+) sensor" of ASICs.
酸敏感离子通道是由细胞外H⁺门控的配体门控阳离子通道。H⁺是最简单的可能配体，对于其他门控离子通道的较大配体而言，必须假定蛋白质三维结构中存在复杂的结合位点，而H⁺原则上可以通过滴定单个氨基酸来门控通道。然而，实验证据表明情况更为复杂。例如，已经表明细胞外Ca²⁺离子与H⁺竞争；可能与酸敏感离子通道细胞外环结合的Ca²⁺离子稳定了通道的关闭状态，并且在通道打开之前必须被取代。在这样的机制中，参与Ca²⁺结合的氨基酸也可能是参与H⁺门控的候选者。在本研究中，我们系统地筛选了酸敏感离子通道1a细胞外区域中40多个保守的带电荷氨基酸对H⁺门控的可能作用。我们鉴定出四个氨基酸，其取代会强烈影响H⁺门控：Glu(63)、His(72)/His(73)和Asp(78)。这些氨基酸在对H⁺敏感的酸敏感离子通道中高度保守，并且是酸敏感离子通道“ H⁺传感器”的候选者。
Zotero 插件