The effects of general anaesthetics on ligand-gated ion channels.

The experimental effort that has been expended in investigating the effects of general anaesthetics on LGICs has been enormous over the past decade. Members of all three LGIC superfamilies have been examined using electrophysiological techniques. Anaesthetics that have been examined include volatile anaesthetics, gaseous anaesthetics, alcohols, i.v. anaesthetics and non-immobilizers. Obsolete anaesthetics (ether, cyclopropane, butane) have been used in order to increase the variability of the structure and polarity of experimental compounds. The tools of molecular biology have been used to make chimeric receptors and to make single-site mutations. Interestingly, this work has been taking place in parallel with efforts to understand the structure of these proteins. Anaesthetic research often stimulates structural research as well as vice versa. There are some common themes in the interactions between anaesthetics and the three superfamilies of LGICs. In many cases, anaesthetics have both inhibitory and potentiating effects on the channels. It is likely that the number of examples of this will increase when experiments are designed to look specifically for one or the other type of effect. So we must conclude that there are multiple binding sites for anaesthetics on LGICs. The degree of inhibition or potentiation is not easily predictable. In retrospect, this is not surprising when we consider that the sensitivity of a channel to anaesthetics can be altered by a single amino-acid mutation. The large structural differences between the cys-loop, glutamate-activated and P2X superfamilies do not lead to large differences in anaesthetic sensitivity. It is the smaller, almost insignificant, changes that do this. This observation that small changes may lead to large effects reinforces the idea that at least some of the interactions between anaesthetics and LGICs are direct drug-protein interactions that are not mediated by the lipids. This review has not addressed the question of whether the effects of anaesthetics seen on LGICs are relevant to anaesthesia. This question cannot really be answered at present. Although potent effects can be observed on the channels themselves, we have only begun to try to understand whether these effects are important for a synapse, a neuronal circuit or the function of an animal's nervous system. We have studied the trees; now we must go on to study the forest and the ecosystem.