Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties.
Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties.
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DOI：
10.1085/jgp.201411172
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Hemmings HC Jr
中科院分区：
文献类型：
--
作者：
Herold KF;Sanford RL;Lee W;Schultz MF;Ingólfsson HI;Andersen OS;Hemmings HC Jr
挥发性麻醉药直接作用于神经元钠通道，不依赖于对脂质双层的影响。尽管全麻药在临床上具有重要意义并得到广泛应用，但其分子作用机制仍知之甚少。异氟醚(ISO)等挥发性麻醉剂被认为通过抑制兴奋性改变神经元功能，并通过与特定蛋白质靶点的直接相互作用促进抑制性神经传递，包括电压门控钠通道(NAV)。许多麻醉药改变了脂双层的性质，这表明离子通道功能也可能通过对脂双层的影响而间接改变。我们比较了ISO和一系列氟苯(FB)模型挥发性麻醉药对NAV功能和脂质双层性质的影响。我们用全细胞电生理学检测了这些药物对神经细胞NAV的影响，并使用基于革兰西丁的荧光分析法检测了这些药物对脂质双层性质的影响，这是一种通过跨双层离子通道检测脂质双层性质变化的功能性分析方法。在临床相关浓度(由最小肺泡浓度定义)下，FBS和ISO都产生脉冲前依赖的NAV抑制，并将失活的电压依赖转移到更超极化的电位，而不影响脂质双分子层的性质，如Granicidin通道所感知的那样。只有在超麻醉剂(毒性)浓度时，ISO才能改变脂质双层性质。这些结果表明，临床上相关浓度的挥发性麻醉药通过与通道蛋白直接相互作用而改变NAV功能，而总体脂双层性质的改变对NAV功能的影响甚微。我们的研究结果进一步表明，临床麻醉并不涉及脂质双层性质的改变。
Volatile anesthetics act directly on neuronal sodium channels, independently of effects on the lipid bilayer. Although general anesthetics are clinically important and widely used, their molecular mechanisms of action remain poorly understood. Volatile anesthetics such as isoflurane (ISO) are thought to alter neuronal function by depressing excitatory and facilitating inhibitory neurotransmission through direct interactions with specific protein targets, including voltage-gated sodium channels (Nav). Many anesthetics alter lipid bilayer properties, suggesting that ion channel function might also be altered indirectly through effects on the lipid bilayer. We compared the effects of ISO and of a series of fluorobenzene (FB) model volatile anesthetics on Nav function and lipid bilayer properties. We examined the effects of these agents on Nav in neuronal cells using whole-cell electrophysiology, and on lipid bilayer properties using a gramicidin-based fluorescence assay, which is a functional assay for detecting changes in lipid bilayer properties sensed by a bilayer-spanning ion channel. At clinically relevant concentrations (defined by the minimum alveolar concentration), both the FBs and ISO produced prepulse-dependent inhibition of Nav and shifted the voltage dependence of inactivation toward more hyperpolarized potentials without affecting lipid bilayer properties, as sensed by gramicidin channels. Only at supra-anesthetic (toxic) concentrations did ISO alter lipid bilayer properties. These results suggest that clinically relevant concentrations of volatile anesthetics alter Nav function through direct interactions with the channel protein with little, if any, contribution from changes in bulk lipid bilayer properties. Our findings further suggest that changes in lipid bilayer properties are not involved in clinical anesthesia.
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
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作者：
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3.4
作者：
Bruno MJ;Rusinova R;Gleason NJ;Koeppe RE 2nd;Andersen OS
通讯作者：
Andersen OS
DOI：
10.1073/pnas.0701015104
发表时间：
2007-06-05
影响因子：
11.1
作者：
Bruno, Michael J.;Koeppe, Roger E., II;Andersen, Olaf S.
通讯作者：
Andersen, Olaf S.