Distinctly different interactions of anesthetic and nonimmobilizer with transmembrane channel peptides.
Although it plays no clinical role in general anesthesia, gramicidin A, a transmembrane channel peptide, provides an excellent model for studying the specific interaction between volatile anesthetics and membrane proteins at the molecular level. We show here that a pair of structurally similar volatile anesthetic and nonimmobilizer (nonanesthetic), 1-chloro-1,2,2-trifluorocyclobutane (F3) and 1, 2-dichlorohexafluorocyclobutane (F6), respectively, interacts differently with the transmembrane peptide. With 400 microM gramicidin A in a vesicle suspension of 60 mM phosphatidylcholine-phosphatidylglycerol (PC/PG), the intermolecular cross-relaxation rate constants between (19)F of F3 and (1)H in the chemical shift regions for the indole and backbone amide protons were 0.0106 +/- 0.0007 (n = 12) and 0.0105 +/- 0.0014 (n = 8) s(-1), respectively. No cross-relaxation was measurable between (19)F of F6 and protons in these regions. Sodium transport study showed that with 75 microM gramicidin A in a vesicle suspension of 66 mM PC/PG, F3 increased the (23)Na apparent efflux rate constant from 149.7 +/- 7.2 of control (n = 3) to 191.7 +/- 12.2 s(-1) (n = 3), and the apparent influx rate constant from 182.1 +/- 15.4 to 222.8 +/- 21.7 s(-1) (n = 3). In contrast, F6 had no effects on either influx or efflux rate. It is concluded that the ability of general anesthetics to interact with amphipathic residues near the peptide-lipid-water interface and the inability of nonimmobilizer to do the same may represent some characteristics of anesthetic-protein interaction that are of importance to general anesthesia.
Tang
P
P
Department of Anesthesiology and Critical Care Medicine, Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. tang@smtp.anes.upmc.edu
Hu
J
J
Liachenko
S
S
Xu
Y
Y
D000595:Amino Acid Sequence; D018681:Anesthetics, General / Q000737:chemistry* / Q000494:pharmacology*; D055592:Biophysical Phenomena; D001703:Biophysics; D017402:Chlorofluorocarbons / Q000737:chemistry / Q000494:pharmacology; D003503:Cyclobutanes / Q000737:chemistry / Q000494:pharmacology; D006096:Gramicidin / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship
D018681:Anesthetics, General; D017402:Chlorofluorocarbons; D003503:Cyclobutanes; D008565:Membrane Proteins; D006096:Gramicidin; C090640:1,2-dichloro-1,2,3,3,4,4-hexafluorocyclobutane; C107485:1-chloro-1,2,2-trifluorocyclobutane; D012964:Sodium