Jp. Dilger et al., EVIDENCE FOR DIRECT ACTIONS OF GENERAL-ANESTHETICS ON AN ION-CHANNEL PROTEIN - A NEW LOOK AT A UNIFIED MECHANISM OF ACTION, Anesthesiology, 81(2), 1994, pp. 431-442
Background: Ion permeation through the nicotinic acetylcholine recepto
r channel is inhibited by general anesthetics. This inhibition could b
e mediated either by binding of anesthetic molecules to the channel pr
otein itself or by the effects of anesthetics on the lipid environment
of the protein. Methods: Patch clamp recording techniques were used t
o investigate the effects of ether and propofol on acetylcholine recep
tor channels in outside-out patches from BC3H-1 cells. The kinetic and
conductance properties of single channels were measured. A rapid perf
usion system was used to make rapid changes in anesthetic concentratio
n during patch clamp recording to determine the kinetics of inhibition
by anesthetics. Results: Ether, isoflurane (results from previous stu
dies), and propofol produce distinct kinetic patterns of single acetyl
choline 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 kineti
cs of inhibition are also different for these anesthetics. Ether (<40
mu s) is faster than isoflurane (300-600 mu s) which is faster than pr
opofol (greater than or equal to 2 ms). Conclusions: These diverse pat
terns can be interpreted in terms of a unitary mechanism in which the
anesthetics interact directly with the channel protein. Each anestheti
c is considered to bind to a site on the protein (perhaps, but not nec
essarily within the pore of the channel) and interrupt the flow of ion
s through the pore. Anesthetics have access to this inhibitory binding
site even when the gate of the channel is dosed. The pattern of chann
el activity induced by an anesthetic is determined by the frequency an
d duration of binding events.