Coupling of agonist binding to channel gating in the GABAA receptor
Coupling of agonist binding to channel gating in the GABAA receptor
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DOI：
10.1038/nature01280
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发表时间：
2003-01-16
期刊：
影响因子：
64.8
通讯作者：
Harrison, NL
中科院分区：
文献类型：
--
作者：
Kash, TL;Jenkins, A;Harrison, NL
神经递质如乙酰胆碱和GABA(伽马氨基丁酸)通过激活属于配体门控离子通道(LGICs)基因超家族的受体来介导快速突触传递(1)。这些通道是五聚体蛋白质，起到信号转导的作用，将化学信息转化为电信号(2)。神经递质通过与配体结合位点(3-7)相互作用激活LGIC，触发蛋白质的构象变化，导致离子通道(8)的开放。这一过程被称为“门控”，发生迅速且可逆，但涉及的分子重排还不是很清楚(9)。在这里，我们证明了LGIC超家族成员GABA(A)受体的最佳门控依赖于细胞外环2和7中带负电荷的Asp 57和Asp 149残基与跨膜2-3连接区的正电荷Lys 279残基之间的静电相互作用。在门控过程中，Asp 149和Lys 279似乎彼此靠近，为配体结合到离子通道的开放提供了一种潜在的机制。
Neurotransmitters such as acetylcholine and GABA (gamma-aminobutyric acid) mediate rapid synaptic transmission by activating receptors belonging to the gene superfamily of ligand-gated ion channels (LGICs)(1). These channels are pentameric proteins that function as signal transducers, converting chemical messages into electrical signals(2). Neurotransmitters activate LGICs by interacting with a ligand-binding site(3-7), triggering a conformational change in the protein that results in the opening of an ion channel(8). This process, which is known as 'gating', occurs rapidly and reversibly, but the molecular rearrangements involved are not well understood(9). Here we show that optimal gating in the GABA(A) receptor, a member of the LGIC superfamily, is dependent on electrostatic interactions between the negatively charged Asp 57 and Asp 149 residues in extracellular loops 2 and 7, and the positively charged Lys 279 residue in the transmembrane 2-3 linker region of the alpha(1)-subunit. During gating, Asp 149 and Lys 279 seem to move closer to one another, providing a potential mechanism for the coupling of ligand binding to opening of the ion channel.