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 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.