Chloride Channel Interactions

This class is named for the target - a chloride channel - and not for the direction of the effect, and its members act at several different channels. Most are GABA-A drugs: the GABA-A receptor is a heteropentameric ligand-gated chloride channel with its GABA sites at the alpha/beta subunit interfaces, and chloride influx through it after opening reduces the neuron's ability to generate an action potential. Benzodiazepines, the anaesthetic alphaxalone and pentobarbital act on it as allosteric activators rather than as agonists at the GABA site, while bicuculline is an antagonist. Other members act on epithelial chloride channels - lubiprostone, ivacaftor, lumacaftor, crofelemer, linaclotide. The macrocyclic lactones act at a different channel again: in the Caenorhabditis elegans glutamate-gated chloride channel, glutamate triggers a rapidly reversible current, whereas ivermectin and other avermectins trigger a permanently open channel configuration, with the ivermectin site at the interface of two glc-1 transmembrane domains.