title: Polychlorocycloalkane insecticide action on GABA-and glycine-dependent chloride flux.
abstract: The inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine directly cause an increase in conductance to Cl- by binding to ligand-operated ion channel receptors at the postsynaptic membranes, so that opening of Cl- channels usually leads to a net hyperpolarization. The GABA(A) receptor has separate but allosterically interacting binding sites for GABA, benzodiazepines, barbiturates, anesthetic steroids and the convulsant picrotoxinin. The GABA(C) receptor also forms a Cl- channel, however its pharmacology differs from that of the GABA(A) receptor. Neurotoxic organochlorine pesticides belonging to the group of polychlorocycloalkanes (cyclodienes and gamma-hexachlorocyclohexane or lindane) induce in mammals an hyperexcitability syndrome that can progress until the production of tonic-clonic convulsions. They act as non-competitive GABA antagonists interacting with the picrotoxinin site both in membranes and in intact cultured neurons, thereby inhibiting the GABA-induced Cl- flux following activation of either GABA(A) or GABA(C) receptors. We also report the effects of polychlorocycloalkanes on glycine-induced 36Cl- flux in primary neuronal cultures. The delta isomer of hexachlorocyclohexane is a depressant compound, that increases the GABA-induced Cl- flux and allosterically increases benzodiazepine binding at the GABA(A) receptor. We discuss the mechanism of action of these compounds in relation to the disruption of ligand-operated Cl- channel receptors and the relevance of their convulsant/depressant actions.
authors.affiliation: Department of Neurochemistry, Institut d'Investigacions Biomédiques de Barcelona, CSIC Jordi Girona 18-26, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Suñol
authors.forename: C
authors.initials: C
authors.lastname: Vale
authors.forename: E
authors.initials: E
authors.lastname: Rodríguez-Farré
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides / Q000633:toxicity*; D015640:Ion Channel Gating / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects*; D018009:Receptors, Glycine / Q000187:drug effects*
chemical_list: D018118:Chloride Channels; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D011963:Receptors, GABA-A; D018009:Receptors, Glycine