Some anesthetics bind and potentiate γ-aminobutyric-acid-type receptors, but no universal mechanism for general anesthesia is known. Furthermore, often encountered complications such as anesthesia induced amnesia are not understood. General anesthetics are hydrophobic molecules easily dissolving into lipid bilayers. Recently, it was shown that general anesthetics perturb phase separation in vesicles extracted from fixed cells. Unclear is whether under physiological conditions general anesthetics induce perturbation of the lipid bilayer, and whether this contributes to the transient loss of consciousness or anesthesia side effects. Here we show that propofol perturbs lipid nanodomains in the outer and inner leaflet of the plasma membrane in intact cells, affecting membrane nanodomains in a concentration dependent manner: 1 μM to 5 μM propofol destabilize nanodomains; however, propofol concentrations higher than 5 μM stabilize nanodomains with time. Stabilization occurs only at physiological temperature and in intact cells. This process requires ARP2/3 mediated actin nucleation and Myosin II activity. The rate of nanodomain stabilization is potentiated by GABA_A receptor activity. Our results show that active nanodomain homeostasis counteracts the initial disruption causing large changes in cortical actin.

Significance statement

General anesthesia is a routine medical procedure with few complications, yet a small number of patients experience side-effects that persist for weeks and months. Very young children are at risk for effects on brain development. Elderly patients often exhibit subsequent amnesia. Here, we show that the general anesthetic propofol perturbs the ultrastructure of the lipid bilayer of the cell membrane in intact cells. Initially propofol destabilized lipid nanodomains. However, with increasing incubation time and propofol concentration, the effect is reversed and nanodomains are further stabilized. We show that this stabilization is caused by the activation of the actin cortex under the membrane. These perturbations of membrane bilayer and cortical actin may explain how propofol affects neuronal plasticity at synapses.

中文翻译：

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异丙酚麻醉过程中膜的纳米域稳态与剂量和温度的关系

某些麻醉剂会结合并增强γ-氨基丁酸型受体，但尚不知道全身麻醉的通用机制。此外，还不了解经常遇到的并发症，例如麻醉引起的健忘症。全身麻醉剂是易于溶解为脂质双层的疏水性分子。近来，显示了全身麻醉剂干扰了从固定细胞中提取的囊泡中的相分离。尚不清楚在生理条件下全身麻醉剂是否会引起脂质双层的扰动，以及这是否会导致短暂的意识丧失或麻醉副作用。在这里，我们显示丙泊酚扰动完整细胞质膜外叶和内叶中的脂质纳米结构域，以浓度依赖的方式影响膜纳米结构域：1μM至5μM的异丙酚使纳米域失去稳定性; 但是，丙泊酚浓度高于5μM会随着时间稳定纳米域。稳定仅在生理温度和完整细胞中发生。此过程需要ARP2 / 3介导的肌动蛋白成核和肌球蛋白II活性。GABA增强了纳米域的稳定速率_一个受体活性。我们的结果表明，活性的纳米域稳态抵消了最初的破坏，从而引起了皮质肌动蛋白的巨大变化。

重要性声明

全身麻醉是一种常规医疗程序，并发症少，但是少数患者会持续数周和数月的副作用。很小的孩子有影响大脑发育的风险。老年患者经常表现出随后的健忘症。在这里，我们表明，普通麻醉剂异丙酚扰动了完整细胞中细胞膜脂质双层的超微结构。最初异丙酚使脂质纳米结构域不稳定。然而，随着温育时间和丙泊酚浓度的增加，该作用被逆转并且纳米域进一步稳定。我们表明，这种稳定是由膜下肌动蛋白皮层的激活引起的。膜双层和皮质肌动蛋白的这些扰动可以解释丙泊酚如何影响突触的神经元可塑性。