INSECTICIDE ACTIONS ON GABA-A RECEPTORS

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DESCRIPTION (provided by applicant): The 3-aminobutyric acid type-A (GABA-A) receptor is the major inhibitory neurotransmitter-gated ion channel in the central nervous system, and an important target for multiple classes of pharmacological agents including the insecticide fipronil. The insecticide fipronil is the active ingredient in many widely used pest control products, and human exposure to these agents, resulting in nausea, vertigo or seizures, has been reported in the medical literature. The proposed work will examine in detail the interactions of fipronil and its metabolite fipronil sulfone with the mammalian GABA-A receptor consisting of 11, 22 and 32L subunits. There are two aims. The first aim is to establish the kinetic mechanisms of action of fipronil and fipronil sulfone on mammalian 112232L GABA-A receptor. The second aim is to determine the mechanisms of resistance to actions of fipronil conferred by mutations in the M2 and M3 transmembrane domains. The results from the work will help to better define the mechanisms of insecticide toxicity, and may be useful in learning how to provide protection from the neurological effects of this widely used insecticide.