Structural consequences of anesthetic and nonimmobilizer interaction with gramicidin A channels.
Although interactions of general anesthetics with soluble proteins have been studied, the specific interactions with membrane bound-proteins that characterize general anesthesia are largely unknown. The structural modulations of anesthetic interactions with synaptic ion channels have not been elucidated. Using gramicidin A as a simplified model for transmembrane ion channels, we have recently demonstrated that a pair of structurally similar volatile anesthetic and nonimmobilizer, 1-chloro-1,2,2-trifluorocyclobutane (F3) and 1,2-dichlorohexafluorocyclobutane (F6), respectively, have distinctly different effects on the channel function. Using high-resolution NMR structural analysis, we show here that neither F3 nor F6 at pharmacologically relevant concentrations can significantly affect the secondary structure of the gramicidin A channel. Although both the anesthetic F3 and the nonimmobilizer F6 can perturb residues at the middle section of the channel deep inside the hydrophobic region in the sodium dodecyl sulfate micelles, only F3, but not F6, can significantly alter the chemical shifts of the tryptophan indole N-H protons near the channel entrances. The results are consistent with the notion that anesthetics cause functional change of the channel by interacting with the amphipathic domains at the peptide-lipid-water interface.
Tang
P
P
Department of Anesthesiology and Critical Care Medicine, Pittsburgh, Pennsylvania 15261, USA. tang@smtp.anes.upmc.edu
Simplaceanu
V
V
Xu
Y
Y
D018681:Anesthetics, General / Q000494:pharmacology*; D055592:Biophysical Phenomena; D001703:Biophysics; D017402:Chlorofluorocarbons / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology; D006096:Gramicidin / Q000737:chemistry*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000737:chemistry* / Q000187:drug effects*; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D017433:Protein Structure, Secondary / Q000187:drug effects; D014364:Tryptophan / Q000737:chemistry; D014867:Water / Q000737:chemistry
D018681:Anesthetics, General; D017402:Chlorofluorocarbons; D003503:Cyclobutanes; D007473:Ion Channels; D008055:Lipids; D008823:Micelles; D014867:Water; D006096:Gramicidin; C090640:1,2-dichloro-1,2,3,3,4,4-hexafluorocyclobutane; C107485:1-chloro-1,2,2-trifluorocyclobutane; D014364:Tryptophan