The lateral pressure profile in membranes: A physical mechanism of general anesthesia
The lateral pressure profile in membranes: A physical mechanism of general anesthesia
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DOI：
10.1021/bi9627323
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发表时间：
1997-03-04
期刊：
影响因子：
2.9
通讯作者：
Cantor, RS
中科院分区：
文献类型：
--
作者：
Cantor, RS
提出了一种全身麻醉的机理，并用晶格统计热力学进行了研究。双层膜的特点是大的侧向应力随膜内深度的变化而变化。两亲性溶质和其他界面活性溶质掺入双分子层，预计会选择性地增加水界面附近的侧压力，并通过降低双分子层中心的侧压力来补偿。全身麻醉可能涉及抑制突触后配体门控膜蛋白离子通道的开放。如果通道打开使蛋白质在水界面附近的横截面积比在双层中间的横截面积更大，那么麻醉引起的界面附近侧压力的增加将使蛋白质的构象平衡向封闭状态转移，因为通道打开将需要更大的功来对抗这种更高的压力。这一假设提供了一个真正的麻醉机制和热力学的理解，而不仅仅是效力与结构或热力学性质的相关性。计算结果与临床麻醉膜浓度下的麻醉效力定性一致，并预测了对水界面几乎没有吸引力的强疏水分子（如全氟碳化合物）的烷醇切断和异常低的效力。
A mechanism of general anesthesia is suggested and investigated using lattice statistical thermodynamics. Bilayer membranes are characterized by large lateral stresses that vary with depth within the membrane. Incorporation of amphiphilic and other interfacially active solutes into the bilayer is predicted to increase the lateral pressure selectively near the aqueous interfaces, compensated by decreased lateral pressure toward the center of the bilayer. General anesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein. If channel opening increases the cross-sectional area of the protein more near the aqueous interface than in the middle of the bilayer, then the anesthetic-induced increase in lateral pressure near the interface will shift the protein conformational equilibrium to favor the closed state, since channel opening will require greater work against this higher pressure. This hypothesis provides a truly mechanistic and thermodynamic understanding of anesthesia, not just correlations of potency with structural or thermodynamic properties. Calculations yield qualitative agreement with anesthetic potency at clinical anesthetic membrane concentrations and predict the alkanol cutoff and anomalously low potencies of strongly hydrophobic molecules with little or no attraction for the aqueous interface, such as perfluorocarbons.