Herold Karl F, Sanford R Lea, Lee William, Andersen Olaf S, Hemmings Hugh C
Department of Anesthesiology, Weill Cornell Medicine, New York, NY 10065.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3109-3114. doi: 10.1073/pnas.1611717114. Epub 2017 Mar 6.
General anesthetics have revolutionized medicine by facilitating invasive procedures, and have thus become essential drugs. However, detailed understanding of their molecular mechanisms remains elusive. A mechanism proposed over a century ago involving unspecified interactions with the lipid bilayer known as the unitary lipid-based hypothesis of anesthetic action, has been challenged by evidence for direct anesthetic interactions with a range of proteins, including transmembrane ion channels. Anesthetic concentrations in the membrane are high (10-100 mM), however, and there is no experimental evidence ruling out a role for the lipid bilayer in their ion channel effects. A recent hypothesis proposes that anesthetic-induced changes in ion channel function result from changes in bilayer lateral pressure that arise from partitioning of anesthetics into the bilayer. We examined the effects of a broad range of chemically diverse general anesthetics and related nonanesthetics on lipid bilayer properties using an established fluorescence assay that senses drug-induced changes in lipid bilayer properties. None of the compounds tested altered bilayer properties sufficiently to produce meaningful changes in ion channel function at clinically relevant concentrations. Even supra-anesthetic concentrations caused minimal bilayer effects, although much higher (toxic) concentrations of certain anesthetic agents did alter lipid bilayer properties. We conclude that general anesthetics have minimal effects on bilayer properties at clinically relevant concentrations, indicating that anesthetic effects on ion channel function are not bilayer-mediated but rather involve direct protein interactions.
全身麻醉药通过促进侵入性手术彻底改变了医学，因此已成为必不可少的药物。然而，对其分子机制的详细了解仍然难以捉摸。一个多世纪前提出的一种机制，涉及与脂质双层的未明确相互作用，即所谓的麻醉作用的单一脂质假说，已受到麻醉药与一系列蛋白质（包括跨膜离子通道）直接相互作用的证据的挑战。然而，膜中的麻醉药浓度很高（10 - 100 mM），并且没有实验证据排除脂质双层在其对离子通道的影响中所起的作用。最近的一个假说提出，麻醉药诱导的离子通道功能变化是由麻醉药分配到双层中引起的双层侧向压力变化导致的。我们使用一种既定的荧光测定法来检测药物引起的脂质双层性质变化，研究了多种化学性质不同的全身麻醉药和相关非麻醉药对脂质双层性质的影响。在临床相关浓度下，所测试的化合物均未充分改变双层性质以在离子通道功能上产生有意义的变化。即使是超麻醉浓度也只引起了最小的双层效应，尽管某些麻醉剂的更高（有毒）浓度确实改变了脂质双层性质。我们得出结论，在临床相关浓度下，全身麻醉药对双层性质的影响最小，这表明麻醉药对离子通道功能的影响不是由双层介导的，而是涉及直接的蛋白质相互作用。
