Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia
Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia
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DOI：
10.1016/j.bpj.2016.06.039
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发表时间：
2016-08-09
影响因子：
3.4
通讯作者：
Veatch, Sarah L.
中科院分区：
文献类型：
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作者：
Machta, Benjamin B.;Gray, Ellyn;Veatch, Sarah L.
不同的分子诱导全身麻醉的效力与它们的疏水性和它们对某些离子通道的作用强烈相关。我们最近观察到，几种n-醇麻醉剂抑制质膜衍生的囊泡的异质性，通过降低相分离的临界温度（Tc）。在这里，我们利用稳定膜异质性的条件，以进一步测试n-醇的麻醉效力和对T-C的影响之间的相关性。首先，我们表明，十六烷醇的行为相反，N-醇麻醉剂膜混合和拮抗乙醇诱导的麻醉在蝌蚪行为测定。其次，我们表明，两个先前描述的“中毒逆转剂”提高T-C和反乙醇的影响，在囊泡，模仿以前的电生理和行为测量的结果。第三，我们发现，升高的静水压力，长期以来已知的逆转麻醉，也提高了T-C囊泡的幅度，抵消丁醇在相关浓度和压力的影响。总之，这些结果表明，Δ T-c预测麻醉效力的n-醇比疏水性在一系列的情况下，支持膜异质性在全身麻醉的机制作用。
Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma membrane-derived vesicles by lowering the critical temperature (T-c) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on T-c. First, we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described "intoxication reversers" raise T-c and counter ethanol's effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises T-c in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that Delta T-c predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.