A discrete site for general anesthetics on a postsynaptic receptor.
A discrete site for general anesthetics on a postsynaptic receptor.
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DOI：
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发表时间：
1995-10
影响因子：
3.6
通讯作者：
S. Forman;K. Miller;G. Yellen
中科院分区：
文献类型：
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作者：
S. Forman;K. Miller;G. Yellen
全身麻醉剂通过一种可能涉及对突触离子通道的影响的机制来抑制中枢神经系统的兴奋性，但其作用部位的基本分子性质尚不清楚。尽管疏水性对于全身麻醉药物效力的重要性早已确定，但仍不确定这些“非特异性”药物是直接作用于膜蛋白还是通过改变脂质膜或脂质-蛋白质界面的物理性质。我们发现乙酰胆碱受体成孔 M2 结构域中的特定突变增强了受体对全身麻醉剂异氟烷、己醇和辛醇的敏感性，表明这些药物通过直接结合到这些残基处或附近的离散蛋白质位点来发挥作用。受体对全身麻醉剂阻断的敏感性随着这些残基疏水性的增加而增加，表明疏水力主导药物与其蛋白质位点的相互作用。此外，辛醇在通道打开后优先抑制野生型和突变型烟碱乙酰胆碱受体，这与药物在受体孔内结合的机制一致。大脑中突触后离子通道上的类似位点可能代表调节意识的全身麻醉目标。
General anesthetics depress central nervous system excitability via a mechanism that probably involves effects on synaptic ion channels, but the fundamental molecular nature of the site where they act is unknown. Although the importance of hydrophobicity for general anesthetic drug potency has long been established, it remains uncertain whether these "nonspecific" drugs act on membrane proteins directly or by modification of the physical properties of the lipid membrane or the lipid-protein interface. We find that specific mutations in the acetylcholine receptor pore-forming M2 domains enhance the sensitivity of the receptor to the general anesthetics isoflurane, hexanol, and octanol, suggesting that these agents act by binding directly to a discrete protein site at or near these residues. The sensitivity of the receptor to block by general anesthetics increases with increased hydrophobicity of these residues, demonstrating that hydrophobic forces dominate the interaction of drugs with their protein site. Furthermore, octanol inhibits both wild-type and mutant nicotinic acetylcholine receptors preferentially after channel opening, which is consistent with a mechanism where drugs bind within the receptor's pore. Similar sites on postsynaptic ion channels in brain may represent general anesthetic targets for modulating consciousness.