title: Differential effects of hexachlorocyclohexane isomers on the GABA receptor subunits expressed in human embryonic kidney cell line.
abstract: We have recently demonstrated by patch clamp experiments that the four isomers of hexachlorocyclohexane (HCH), alpha-, beta-, gamma- and delta-HCH insecticides, modulated the kinetics of the GABAA receptor-chloride channel complex of rat dorsal root ganglion neurons. The present paper reports the differential effects of HCH isomers of the GABA-induced chloride currents in three combinations of alpha, beta and gamma subunits of GABAA receptor expressed in human embryonic kidney cells. When co-applied with GABA, gamma-HCH strongly suppressed the peak amplitude of GABA-induced current, and delta-HCH strongly enhanced it in the alpha 1 beta 2 gamma 2s, alpha 1 beta 2, alpha 6 beta 2 gamma 2s combinations in a dose-dependent manner. There was little or no difference in the dose dependence of the effects between gamma- and delta-HCH in any of the three subunit combinations. However, alpha- and beta-HCH showed differential effects on GABA-induced chloride currents in the three subunit combinations tested. alpha-HCH showed enhancing effects on the peak current in alpha 1 beta 2 gamma 2s, small enhancing effects on alpha 1 beta 2, and biphasic effects on alpha 6 beta 2 gamma 2s subunit combinations. beta-HCH had little or no effect on the peak current in alpha 1 beta 2 gamma 2s and alpha 1 beta 2 combinations, but suppressed currents in the alpha 6 beta2 gamma 2s subunit combination in a dose-dependent manner. The differential actions of HCH isomers may produce variable effects on different regions of the nervous systems and in different species of animals.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: C S
authors.initials: CS
authors.lastname: Huang
authors.forename: B J
authors.initials: BJ
authors.lastname: Hamilton
authors.forename: D B
authors.initials: DB
authors.lastname: Carter
authors.forename: T
authors.initials: T
authors.lastname: Narahashi
mesh_terms: D002460:Cell Line; D002712:Chlorides / Q000502:physiology; D004357:Drug Synergism; D004553:Electric Conductivity; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D007536:Isomerism; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D002712:Chlorides; D007306:Insecticides; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane