The nonproton ligand of acid-sensing ion channel 3 activates mollusk-specific FaNaC channels via a mechanism independent of the native FMRFamide peptide.
The nonproton ligand of acid-sensing ion channel 3 activates mollusk-specific FaNaC channels via a mechanism independent of the native FMRFamide peptide.
复制标题
酸敏感离子通道 3 的非质子配体通过独立于天然 FMRFamide 肽的机制激活软体动物特异性 FaNaC 通道。
DOI：
10.1074/jbc.m117.814707
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发表时间：
2017
影响因子：
4.8
通讯作者：
Yu Ye
中科院分区：
文献类型：
--
作者：
Yang Xiao-Na;Niu You-Ya;Liu Yan;Yang Yang;Wang Jin;Cheng Xiao-Yang;Liang Hong;Wang Heng-Shan;Hu You-Min;Lu Xiang-Yang;Zhu Michael X;Xu Tian-Le;Tian Yun;Yu Ye
离子通道的变性蛋白/上皮钠通道（DEG/ENaC）超家族包含具有多种功能的亚家族，这些功能对于许多生理和病理过程是基础的，从突触传递到癫痫发生。在哺乳动物中缺乏一些DEG/ENaCs亚家族的直系同源物，如FMRFamide肽激活钠通道（FaNaCs），这只在软体动物中发现，表明不同的亚家族在进化早期就分化了。我们最近报道，非质子激动剂2-胍-4-甲基喹唑啉（GMQ）激活酸敏感离子通道（ASIC），DEG/ENaC亚家族主要在哺乳动物中，在没有酸中毒。在这里，我们表明GMQ也可以直接激活软体动物特异性FaNaCs。离子选择性和单位电导的差异以及关键残基取代的影响表明，GMQ和FMRFamide通过不同的机制激活FaNaCs。在FaNaC亚家族中存在两种激活机制，在DEG/ENaCs的进化早期出现分歧，这表明双门控是这个超家族中的一个古老特征。值得注意的是，GMQ门控模式仍然保留在哺乳动物ASIC亚家族中，而FMRFamide介导的通道门控在进化过程中丢失。这意味着GMQ激活可能是哺乳动物DEG/ENaCs功能所必需的。我们的研究结果提供了新的见解DEG/ENaCs的演变，并可能促进其内源性激动剂的发现和表征。
The degenerin/epithelial sodium channel (DEG/ENaC) superfamily of ion channels contains subfamilies with diverse functions that are fundamental to many physiological and pathological processes, ranging from synaptic transmission to epileptogenesis. The absence in mammals of some DEG/ENaCs subfamily orthologues such as FMRFamide peptide–activated sodium channels (FaNaCs), which have been identified only in mollusks, indicates that the various subfamilies diverged early in evolution. We recently reported that the nonproton agonist 2-guanidine-4-methylquinazoline (GMQ) activates acid-sensing ion channels (ASICs), a DEG/ENaC subfamily mainly in mammals, in the absence of acidosis. Here, we show that GMQ also could directly activate the mollusk-specific FaNaCs. Differences in ion selectivity and unitary conductance and effects of substitutions at key residues revealed that GMQ and FMRFamide activate FaNaCs via distinct mechanisms. The presence of two activation mechanisms in the FaNaC subfamily diverging early in the evolution of DEG/ENaCs suggested that dual gating is an ancient feature in this superfamily. Notably, the GMQ-gating mode is still preserved in the mammalian ASIC subfamily, whereas FMRFamide-mediated channel gating was lost during evolution. This implied that GMQ activation may be essential for the functions of mammalian DEG/ENaCs. Our findings provide new insights into the evolution of DEG/ENaCs and may facilitate the discovery and characterization of their endogenous agonists.