Transmitter-activated ion channels as the target of chemical agents

Abstract

The transmitter-activated ion channels are known to be important target sites of a variety of therapeutic and toxic agents. The GABA-activated chloride channel has been shown to be modulated by general anesthetics, alcohols, and the pyrethroid, cyclodiene and lindane insecticides. The general anesthetics halothane, enflurane and isoflurane greatly augmented the GABA-activated current before desensitization took place, and suppressed it after desensitization at clinically relevant concentrations equivalent to 1-2 minimum alveolar concentrations. The stimulating effect appears to be a mechanism of general anesthesia. It seems that general anesthetics have a specific affinity for the GABA receptor-channel complex. Ethanol also augmented the GABA-activated peak chloride current with little or no effect on the desensitized sustained current. Longer chain alcohols n-butanol, n-hexanol, n-octanol, and n-decanol also exerted the same type of effect, with the potency and efficacy increasing with lengthening of the carbon chain. The GABA receptor-channel complex has also been shown to be an important target site of certain insecticides. The type II pyrethroids deltamethrin and fenvalerate augmented the GABA-activated peak chloride current when applied concurrently with GABA, but the effect was diminished as the pyrethroids were applied for long periods of time prior to GABA application. The latter effect might explain the controversy in the literature regarding the pyrethroid action on the GABA system. The type I pyrethroid allethrin suppressed the GABA-activated peak chloride current when co-applied with GABA. Both types of pyrethroids suppressed the N-methyl-d-aspartate-induced current. Lindane and the cyclodienes dieldrin, endrin, heptachlor-epoxide, and isobenzan suppressed the GABA-activated chloride current. These effects can account for the convulsant action of lindane and the cyclodienes.