Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes.
Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes.
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DOI：
10.1017/s0033583513000061
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发表时间：
2013-11
影响因子：
6.1
通讯作者：
Unwin, Nigel
中科院分区：
文献类型：
--
作者：
Unwin, Nigel
位于神经肌肉接头的烟碱型乙酰胆碱(ACh)受体是一种神经递质门控离子通道，通过进化进行微调，以最大的效率和速度将化学信号转换为电信号。它由三个相似的和两个相同的多肽链组成，围绕着一个狭窄的膜孔排列成一个环。这个组件的设计核心是在毛孔中有一个疏水门，距离ACh结合的细胞外域位置超过50°。尽管在过去的几十年里，人们对受体的分子性质进行了深入的研究，但直到最近才出现了揭示其复杂结构的结构，并阐明了ACh进入结合位点是如何打开遥远的大门的。从鱼雷射线的(肌源性)电器官中分离出来的突触后膜支持了大多数结构研究：这些膜形成管状小泡，其受体排列在规则的表面晶格上，可以在冷冻的生理溶液中直接成像。电子结晶学技术的进步也很重要，能够分析未反应的管或与ACh短暂反应的管中受体的封闭和开放通道形式。这两种形式之间的结构差异表明，所有五个亚基都参与了协调的构象变化，传递ACh与门结合的效果，但其中三个亚基(αγ，β和δ)起主导作用。相对面孔衬里α螺旋的弯曲是决定闸门关闭/打开状态的主要运动。这些结果与生化、生物物理和其他结构研究的结果一起，可以对该受体及其在突触中的作用模式进行综合描述。
The nicotinic acetylcholine (ACh) receptor, at the neuromuscular junction, is a neurotransmitter-gated ion channel that has been fine-tuned through evolution to transduce a chemical signal into an electrical signal with maximum efficiency and speed. It is composed from three similar and two identical polypeptide chains, arranged in a ring around a narrow membrane pore. Central to the design of this assembly is a hydrophobic gate in the pore, more than 50 Å away from sites in the extracellular domain where ACh binds. Although the molecular properties of the receptor have been explored intensively over the last few decades, only recently have structures emerged revealing its complex architecture and illuminating how ACh entering the binding sites opens the distant gate. Postsynaptic membranes isolated from the (muscle-derived) electric organ of the Torpedo ray have underpinned most of the structural studies: the membranes form tubular vesicles having receptors arranged on a regular surface lattice, which can be imaged directly in frozen physiological solutions. Advances in electron crystallographic techniques have also been important, enabling analysis of the closed- and open-channel forms of the receptor in unreacted tubes or tubes reacted briefly with ACh. The structural differences between these two forms show that all five subunits participate in a concerted conformational change communicating the effect of ACh binding to the gate, but that three of them (αγ, β and δ) play a dominant role. Flexing of oppositely facing pore-lining α-helices is the principal motion determining the closed/open state of the gate. These results together with the findings of biochemical, biophysical and other structural studies allow an integrated description of the receptor and of its mode of action at the synapse.