Alakoskela Juha-Matti, Covey Douglas F, Kinnunen Paavo K J
Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Biochemistry, P.O. Box 63, 00014 University of Helsinki, Finland.
Biochim Biophys Acta. 2007 Jan;1768(1):131-45. doi: 10.1016/j.bbamem.2006.07.011. Epub 2006 Jul 26.
The most important target protein for many anesthetics, including volatile and steroid anesthetics, appears to be the type A gamma-amino butyric acid receptor (GABA(A)R), yet direct binding remains to be demonstrated. Hypotheses of lipid-mediated anesthesia suggest that lipid bilayer properties are changed by anesthetics and that this in turn affects the functions of proteins. While other data could equally well support direct or lipid-mediated action, enantiomeric specificity displayed by some anesthetics is not reflected in their interactions with lipids. In the present study, we studied the effects of two pairs of anesthetic steroid enantiomers on bilayers of several compositions, measuring potentially relevant physical properties. For one of the pairs, allopregnanolone and ent-allopregnanolone, the natural enantiomer is 300% more efficacious as an anesthetic, while for the other, pregnanolone and ent-pregnanolone, there is little difference in anesthetic potency. For each enantiomer pair, we could find no differences. This strongly favors the view that the effects of these anesthetics on lipid bilayers are not relevant for the main features of anesthesia. These steroids also provide tools to distinguish in general the direct binding of steroids to proteins from lipid-mediated effects.
包括挥发性麻醉剂和甾体麻醉剂在内的许多麻醉剂，其最重要的靶蛋白似乎是A型γ-氨基丁酸受体（GABA(A)R），但直接结合仍有待证实。脂质介导麻醉的假说表明，麻醉剂会改变脂质双分子层的特性，进而影响蛋白质的功能。虽然其他数据同样能很好地支持直接作用或脂质介导的作用，但某些麻醉剂表现出的对映体特异性并未在它们与脂质的相互作用中体现出来。在本研究中，我们研究了两对麻醉甾体对映体对几种组成的双分子层的影响，测量了潜在相关的物理性质。对于其中一对，别孕烯醇酮和对映体别孕烯醇酮，天然对映体作为麻醉剂的效力要高出300%，而对于另一对，孕烯醇酮和对映体孕烯醇酮，麻醉效力几乎没有差异。对于每对对映体，我们都没有发现差异。这有力地支持了这样一种观点，即这些麻醉剂对脂质双分子层的影响与麻醉的主要特征无关。这些甾体还提供了工具，一般来说可用于区分甾体与蛋白质的直接结合和脂质介导的效应。
