title: Methylmercury induces an initial increase in GABA-evoked currents in Xenopus oocytes expressing α1and α6subunit-containing GABAAreceptors.
abstract: Early onset effects of methylmercury (MeHg) on recombinant α1β2γ2Sor α6β2γ2Ssubunit-containing GABAAreceptors were examined. These are two of the most prevalent receptor types found in cerebellum-a consistent target of MeHg-induced neurotoxicity. Heterologously expressed receptors were used in order to: (1) isolate receptor-mediated events from extraneous effects of MeHg due to stimulation of the receptor secondary to increased release of GABA seen with MeHg in neurons in situ and (2) limit the phenotypes of GABAAreceptors present at one time. Initial changes in IGABAin Xenopus laevis oocytes expressing either α1β2γ2Sor α6β2γ2Sreceptors were compared during continuous bath application of MeHg. A time-dependent increase in IGABAmediated by both receptor subtypes occurred following the first 25-30min of MeHg (5μM) exposure. In α6β2γ2Scontaining receptors, the MeHg-induced increase in IGABAwas less pronounced compared to that mediated by α1β2γ2Scontaining receptors, although the pattern of effects was generally similar. Washing with MeHg-free solution reversed the increase in current amplitude. Application of bicuculline at the time of peak potentiation of IGABArapidly and completely reversed the MeHg-induced currents. Therefore these MeHg-increased inward currents are mediated specifically by the two subtypes of GABAAreceptors and appear to entail direct actions of MeHg on the receptor. However bicuculline did not affect stimulation by MeHg of oocyte endogenous Cl--mediated current, which presumably results from increased [Ca2+]i. Thus, MeHg initially potentiates IGABAin oocytes expressing either α1β2γ2Sor α6β2γ2Sreceptors prior to its more defined later effects, suggesting that MeHg may initially interact directly with GABAAreceptors in a reversible manner to cause this potentiation.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Tidao
authors.initials: T
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Hajela
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Shuan W
authors.initials: SW
authors.lastname: Philips
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. Electronic address: atchiso1@msu.edu.
authors.forename: William D
authors.initials: WD
authors.lastname: Atchison
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000494:pharmacology*; D009544:Niflumic Acid; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D058787:GABA-A Receptor Antagonists; D008767:Methylmercury Compounds; D021122:Protein Subunits; D011963:Receptors, GABA-A; D009544:Niflumic Acid; D005680:gamma-Aminobutyric Acid; C004925:methylmercuric chloride; D001640:Bicuculline
keywords: GABA(A) receptor; Heterologous expression; Methylmercury; α(1) and α(6) subunit