Membrane-mediated effect on ion channels induced by the anesthetic drug ketamine.
Anesthetic drugs have been in use for over 160 years in surgery, but their mode of action remains largely unresolved. We have studied the effect of (R)-(-)-ketamine on the biophysical properties of lipid model membranes composed of palmitoyloleoylphosphatidylcholine by a combination of X-ray diffraction and all-atom molecular dynamics simulations. In agreement with several previous studies, we do not find significant changes to the membrane thickness and lateral area per lipid up to 8 mol % ketamine content. However, we observed that the insertion of ketamine within the lipid/water interface caused significant changes of lateral pressure and a pressure shift toward the center of the bilayer. The changes are predicted to be large enough to affect the opening probability of ion channels as derived for two protein models. Depending on the protein model, we found inhibition values of IC(50) = 2 mol % and 18 mol % ketamine, corresponding to approximately 0.08 and 0.9 muM concentrations in the blood circulation, respectively. This compares remarkably well with clinical applied concentrations. We thus provide evidence for a lateral pressure mediated mode of anesthesia, first proposed more than 10 years ago.
Department of Heath & Environment, Austrian Institute of Technology, A-2444 Seibersdorf, Austria.
Hansjörg
H
Jerabek
Georg
G
Pabst
Michael
M
Rappolt
Thomas
T
Stockner
D000777:Anesthetics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010743:Phospholipids / Q000378:metabolism; D011312:Pressure; D053838:Scattering, Small Angle; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D000777:Anesthetics; D007473:Ion Channels; D008565:Membrane Proteins; D010743:Phospholipids; D007649:Ketamine