Cantor R S
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA.
Biochemistry. 1997 Mar 4;36(9):2339-44. doi: 10.1021/bi9627323.
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.
利用晶格统计热力学提出并研究了全身麻醉的一种机制。双层膜的特征在于其大的侧向应力会随膜内深度而变化。预计将两亲性和其他界面活性溶质掺入双层中会选择性地增加靠近水界面处的侧向压力，并通过朝向双层中心的侧向压力降低来补偿。全身麻醉可能涉及抑制突触后配体门控膜蛋白中离子通道的开放。如果通道开放在靠近水界面处比在双层中间增加蛋白质的横截面积更多，那么麻醉剂引起的界面附近侧向压力的增加将使蛋白质构象平衡向有利于关闭状态的方向移动，因为通道开放将需要克服这种更高压力做更多的功。该假设提供了对麻醉的真正机械和热力学理解，而不仅仅是效力与结构或热力学性质的相关性。计算结果在临床麻醉膜浓度下与麻醉效力达成定性一致，并预测了链烷醇截止值以及对水界面几乎没有吸引力或没有吸引力的强疏水分子（如全氟化碳）异常低的效力。
