Evidence for direct actions of general anesthetics on an ion channel protein. A new look at a unified mechanism of action.
BACKGROUND
Ion permeation through the nicotinic acetylcholine receptor channel is inhibited by general anesthetics. This inhibition could be mediated either by binding of anesthetic molecules to the channel protein itself or by the effects of anesthetics on the lipid environment of the protein.


METHODS
Patch clamp recording techniques were used to investigate the effects of ether and propofol on acetylcholine receptor channels in outside-out patches from BC3H-1 cells. The kinetic and conductance properties of single channels were measured. A rapid perfusion system was used to make rapid changes in anesthetic concentration during patch clamp recording to determine the kinetics of inhibition by anesthetics.


RESULTS
Ether, isoflurane (results from previous studies), and propofol produce distinct kinetic patterns of single acetylcholine receptor channel activity. Ether reduces the apparent current amplitude of channels, isoflurane induces flickering channel activity and propofol merely decreases the open time of the channel. The kinetics of inhibition are also different for these anesthetics. Ether (< 40 microseconds) is faster than isoflurane (300-600 microseconds) which is faster than propofol (> or = 2 ms).


CONCLUSIONS
These diverse patterns can be interpreted in terms of a unitary mechanism in which the anesthetics interact directly with the channel protein. Each anesthetic is considered to bind to a site on the protein (perhaps, but not necessarily within the pore of the channel) and interrupt the flow of ions through the pore. Anesthetics have access to this inhibitory binding site even when the gate of the channel is closed. The pattern of channel activity induced by an anesthetic is determined by the frequency and duration of binding events.
Dilger
J P
JP
Department of Anesthesiology, School of Medicine, University at Stony Brook, New York.
Vidal
A M
AM
Mody
H I
HI
Liu
Y
Y
D002478:Cells, Cultured; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology*
D007473:Ion Channels; D011978:Receptors, Nicotinic; D007530:Isoflurane; D015742:Propofol