title: Lack of enantiomeric specificity in the effects of anesthetic steroids on lipid bilayers.
abstract: 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.
authors.affiliation: Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Biochemistry, P.O. Box 63, 00014 University of Helsinki, Finland. Juha-Matti.Alakoskela@helsinki.fi
authors.forename: Juha-Matti
authors.initials: JM
authors.lastname: Alakoskela
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Paavo K J
authors.initials: PK
authors.lastname: Kinnunen
mesh_terms: D000777:Anesthetics / Q000737:chemistry / Q000494:pharmacology*; D002152:Calorimetry, Differential Scanning; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000187:drug effects*; D005456:Fluorescent Dyes; D006801:Humans; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects; D008968:Molecular Conformation; D044367:Phase Transition / Q000187:drug effects; D011280:Pregnanolone / Q000737:chemistry; D011726:Pyridinium Compounds; D018079:Receptors, GABA / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013696:Temperature; D014867:Water / Q000737:chemistry
chemical_list: C089669:1-(3-sulfonatopropyl)-4-(beta-(2-(di-n-octylamino)-6-naphthyl)vinyl)pyridinium betaine; D000777:Anesthetics; D005456:Fluorescent Dyes; C087200:GABA-C receptor; D008051:Lipid Bilayers; D008563:Membrane Lipids; D011726:Pyridinium Compounds; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D013256:Steroids; D014867:Water; D011280:Pregnanolone