A Nonproton Ligand Sensor in the Acid-Sensing Ion Channel
A Nonproton Ligand Sensor in the Acid-Sensing Ion Channel
复制标题
酸敏感离子通道中的非质子配体传感器
DOI：
10.1016/j.neuron.2010.09.001
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发表时间：
2010-10-07
期刊：
影响因子：
16.2
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
--
作者：
Yu, Ye;Chen, Zhi;Xu, Tian-Le
酸感离子通道（asic）一直被认为是细胞外质子（H+）门控阳离子通道，外周ASIC3通道似乎是酸性疼痛的天然传感器。在这里，我们报道在ASIC3上发现了一个非质子传感器。我们首先证明了2-胍-4-甲基喹唑啉（GMQ）在正常ph下引起持续的ASIC3通道激活。使用GMQ作为探针，结合诱变和共价修饰分析，我们发现了一个配体传感器，该传感器由ASIC3通道胞外“棕榈”结构域E423和E79周围的残基排列，这对于非质子激活剂的激活至关重要。此外，我们发现GMQ激活感觉神经元并以ASIC3依赖的方式引起疼痛相关行为，这表明非质子配体激活ASIC的功能意义。因此，质子以外的天然配体可以在生理和病理条件下通过非质子配体传感器激活asic，独立于突然和明显的酸中毒而激活通道。
Acid-sensing ion channels (ASICs) have long been considered as extracellular proton (H+)-gated cation channels, and peripheral ASIC3 channels seem to be a natural sensor of acidic pain. Here, we report the identification of a nonproton sensor on ASIC3. We show first that 2-guanidine-4-methylquinazoline (GMQ) causes persistent ASIC3 channel activation at the normal pH. Using GMQ as a probe and combining mutagenesis and covalent modification analysis, we then uncovered a ligand sensor lined by residues around E423 and E79 of the extracellular "palm" domain of the ASIC3 channel that-is crucial for activation by nonproton activators. Furthermore, we show that GMQ activates sensory neurons and causes pain-related behaviors in an ASIC3,dependent manner, indicating the functional significance of ASIC activation by nonproton ligands. Thus, natural ligands beyond protons may activate ASICs under physiological and pathological conditions through the nonproton ligand sensor, serving for channel activation independent of abrupt and marked acidosis.