An arginine residue in the outer segment of hASIC1a TM1 affects both proton affinity and channel desensitization.
An arginine residue in the outer segment of hASIC1a TM1 affects both proton affinity and channel desensitization.
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DOI：
10.1085/jgp.202012802
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发表时间：
2021-05-03
期刊：
影响因子：
--
通讯作者：
Canessa CM
中科院分区：
文献类型：
--
作者：
Chen Z;Kuenze G;Meiler J;Canessa CM
酸敏感离子通道（ASIC）在中枢和外周神经系统中发挥着重要作用。在这篇论文中，Chen等人表明，人类ASIC的单个精氨酸的变化既影响质子介导的门控的功效，又延迟通道的脱敏。酸敏感离子通道（ASIC）对中枢和外周神经系统中pH的变化做出反应，并参与突触可塑性和疼痛感知。尽管它们的结构处于不同的构象状态，但理解质子介导的门控机制仍然是难以捉摸的。我们在这里报告说，R64，精氨酸位于外段的第一个跨膜结构域的所有三种亚型的哺乳动物ASIC，显着影响的表观质子亲和力的激活和脱敏程度的开放和预开放状态。Rosetta对自由能变化的计算预测，hASIC 1a中的R64被芳香族残基取代会使闭合构象不稳定，同时使开放构象稳定。因此，F64增强了质子介导的hASIC 1a门控的功效，这增加了表观pH 50，并且当仅一个或两个亚基被激活时促进通道开放。F64还延长了开放事件的持续时间，从而使通道在延长的时间段内保持开放并减少低pH诱导的脱敏。我们的研究结果表明，pH 50等于或大于pH 7.2-7.1的质子传感器的激活打开F64 hASIC 1a，而由于R64施加的高激活能，它诱导野生型通道中的稳态脱敏，这阻止了孔的打开。总之，这些发现表明，高亲和力质子传感器的激活和共同的门控机制可能介导hASIC 1a的激活和稳态脱敏过程。
Acid-sensing ion channels (ASIC) play central roles in the central and peripheral nervous systems. In this paper, Chen et al. show that changes to a single arginine of a human ASIC both affect the efficacy of proton-mediated gating and delay the desensitization of the channel. Acid-sensing ion channels (ASICs) respond to changes in pH in the central and peripheral nervous systems and participate in synaptic plasticity and pain perception. Understanding the proton-mediated gating mechanism remains elusive despite the of their structures in various conformational states. We report here that R64, an arginine located in the outer segment of the first transmembrane domain of all three isoforms of mammalian ASICs, markedly impacts the apparent proton affinity of activation and the degree of desensitization from the open and preopen states. Rosetta calculations of free energy changes predict that substitutions of R64 in hASIC1a by aromatic residues destabilize the closed conformation while stabilizing the open conformation. Accordingly, F64 enhances the efficacy of proton-mediated gating of hASIC1a, which increases the apparent pH50 and facilitates channel opening when only one or two subunits are activated. F64 also lengthens the duration of opening events, thus keeping channels open for extended periods of time and diminishing low pH-induced desensitization. Our results indicate that activation of a proton sensor(s) with pH50 equal to or greater than pH 7.2–7.1 opens F64hASIC1a, whereas it induces steady-state desensitization in wildtype channels due to the high energy of activation imposed by R64, which prevents opening of the pore. Together, these findings suggest that activation of a high-affinity proton-sensor(s) and a common gating mechanism may mediate the processes of activation and steady-state desensitization of hASIC1a.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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