Prying open a glutamate receptor gate.
Prying open a glutamate receptor gate.
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撬开谷氨酸受体大门。
DOI：
10.1085/jgp.201812312
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Wollmuth,LonnieP
中科院分区：
文献类型：
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作者：
Wollmuth,LonnieP
离子通道从封闭的、不导电的构象转变为开放的、导电的构象，这一过程称为门控，是生理学的基础。在开放状态下，当形成充满水的离子传导通路时，离子穿过膜以影响膜、细胞并最终影响器官生理学。在这一期的普通生理学杂志中，Wilding和Huettner探讨了谷氨酸门控离子通道中的门控过程，谷氨酸门控离子通道是一种普遍存在的功能关键的离子通道。他们发现了一个非常令人困惑但又非常有用的东西：一种撬开大门的手段。离子型谷氨酸受体（iGluRs）是配体门控的离子通道，由神经递质谷氨酸（中枢神经系统中最重要的神经递质）门控。iGluRs中离子通道的核心与K+通道具有同源性。主要的孔衬跨膜区段M3区段与K+通道中的TM 2或S6同源（Wo和Oswald，1995）。然而，iGluR的取向相对于K+通道是反向的，因此M3区段在其细胞外末端形成束螺旋交叉或门，其在闭合状态下阻塞离子通量（Chang和Kuo，2008; Sobolevsky等人，2009; Ladislav等人，2018年）。激动剂与细胞外配体结合结构域（LBD）结合，将M3片段拉离孔的中心轴，从而导致离子通道开放（Twomey和Sobolevsky，2018）。至少对于一种亚型，iGluR的闭合和开放状态的结构存在，并且它们在理解iGluR中的离子通道门控机制方面具有变革性（图1，A和B; Chen等人，2017; Twomey等人，2017年）。尽管如此，这些结构限定了终点，并且没有揭示M3区段以及其他跨膜区段如何重排以从闭合状态转变为开放状态的动力学和能量学。为了解决孔开放期间M3跨膜片段的动力学问题，Wilding和Huettner（2018）利用了半胱氨酸的化学性质。用半胱氨酸取代单个残基是研究离子通道动力学的宝贵方法，因为其巯基侧链是
The transition of ion channels from the closed, nonconducting conformation to the open, conducting conformation—a process referred to as gating—is fundamental to physiology. It is in the open state, when the water-filled ion conduction pathway is formed, that ions cross the membrane to impact membrane, cellular, and ultimately, organ physiology. In this issue of the Journal of General Physiology, Wilding and Huettner probe this gating process in glutamate-gated ion channels, a ubiquitous and functionally critical class of ion channels. They discover something quite perplexing yet extremely useful: a means to pry open a gate.Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are gated by the neurotransmitter glutamate, the most prominent neurotransmitter in the central nervous system. The core of the ion channel in iGluRs shares homology with K+ channels. The major pore-lining transmembrane segment, the M3 segment, is homologous to TM2 or S6 in K+ channels (Wo and Oswald, 1995). However, the orientation of iGluRs is inverted with respect to K+ channels, so the M3 segments form a bundle helical crossing, or a gate, at their extracellular ends, which occludes the flux of ions in the closed state (Chang and Kuo, 2008; Sobolevsky et al., 2009; Ladislav et al., 2018). Agonist binding to the extracellular ligand-binding domain (LBD) pulls the M3 segments away from the central axis of the pore and therefore leads to ion channel opening (Twomey and Sobolevsky, 2018). Structures exist of the closed and open states of iGluRs, at least for one subtype, and they have been transformative in understanding the mechanism of ion channel gating in iGluRs (Fig. 1, A and B; Chen et al., 2017; Twomey et al., 2017). Still, these structures define endpoints and do not reveal the dynamics and energetics of how the M3 segments, as well as other transmembrane segments, are rearranged to transition from the closed to the open state. To address the dynamics of the M3 transmembrane segments during pore opening, Wilding and Huettner (2018) took advantage of the chemistry of cysteine. Substituting individual residues with cysteine has been an invaluable approach to study the dynamics of ion channels because its thiol side chain is