Structural consequences of anesthetic and nonimmobilizer interaction with gramicidin A channels

Although interactions of general anesthetics with soluble proteins have bee n studied, the specific interactions with membrane bound-proteins that char acterize general anesthesia are largely unknown. The structural modulations of anesthetic interactions with synaptic ion channels have not been elucid ated. Using gramicidin A as a simplified model for transmembrane ion channe ls, we have recently demonstrated that a pair of structurally similar volat ile 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 struct ural analysis, we show here that neither F3 nor F6 at pharmacologically rel evant concentrations can significantly affect the secondary structure of th e gramicidin A channel. Although both the anesthetic F3 and the nonimmobili zer F6 can perturb residues at the middle section of the channel deep insid e the hydrophobic region in the sodium dodecyl sulfate micelles, only F3, b ut not F6, can significantly alter the chemical shifts of the tryptophan in dole N-H protons near the channel entrances. The results are consistent wit h the notion that anesthetics cause functional change of the channel by int eracting with the amphipathic domains at the peptide-lipid-water interface.