title: Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels.
abstract: BACKGROUND
  Both propofol and thiamylal inhibit adenosine triphosphate-sensitive potassium (KATP) channels. In the current study, the authors investigated the effects of these anesthetics on the activity of recombinant sarcolemmal KATP channels encoded by inwardly rectifying potassium channel (Kir6.1 or Kir6.2) genes and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) genes.
  
  
  METHODS
  The authors used inside-out patch clamp configurations to investigate the effects of propofol and thiamylal on the activity of recombinant KATP channels using COS-7 cells transfected with various types of KATP channel subunits.
  
  
  RESULTS
  Propofol inhibited the activities of the SUR1/Kir6.2 (EC50 = 77 microm), SUR2A/Kir6.2 (EC50 = 72 microm), and SUR2B/Kir6.2 (EC50 = 71 microm) channels but had no significant effects on the SUR2B/Kir6.1 channels. Propofol inhibited the truncated isoform of Kir6.2 (Kir6.2DeltaC36) channels (EC50 = 78 microm) that can form functional KATP channels in the absence of SUR molecules. Furthermore, the authors identified two distinct mutations R31E (arginine residue at position 31 to glutamic acid) and K185Q (lysine residue at position 185 to glutamine) of the Kir6.2DeltaC36 channel that significantly reduce the inhibition of propofol. In contrast, thiamylal inhibited the SUR1/Kir6.2 (EC50 = 541 microm), SUR2A/Kir6.2 (EC50 = 248 microm), SUR2B/Kir6.2 (EC50 = 183 microm), SUR2B/Kir6.1 (EC50 = 170 microm), and Kir6.2DeltaC36 channels (EC50 = 719 microm). None of the mutants significantly affects the sensitivity of thiamylal.
  
  
  CONCLUSIONS
  These results suggest that the major effects of both propofol and thiamylal on KATP channel activity are mediated via the Kir6.2 subunit. Site-directed mutagenesis study suggests that propofol and thiamylal may influence Kir6.2 activity by different molecular mechanisms; in thiamylal, the SUR subunit seems to modulate anesthetic sensitivity.
authors.affiliation: Department of Anesthesiology, Tokushima University School of Medicine, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. haf26740@ams.odn.ne.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawano
authors.forename: Shuzo
authors.initials: S
authors.lastname: Oshita
authors.forename: Akira
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitahata
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
mesh_terms: D018528:ATP-Binding Cassette Transporters; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D008967:Molecular Biology; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000235:genetics; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013840:Thiamylal / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D018686:Anesthetics, Intravenous; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D013840:Thiamylal; D020110:Pinacidil; D003981:Diazoxide; D005905:Glyburide; D015742:Propofol