Methylmercury induces an initial increase in GABA-evoked currents inXenopusoocytes expressing α1 and α6 subunit-containing GABAA receptors

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Abstract

Early onset effects of methylmercury (MeHg) on recombinant α1β2γ2S or α6β2γ2S subunit-containing GABAA receptors 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 GABAA receptors present at one time. Initial changes in IGABA in Xenopus laevis oocytes expressing either α1β2γ2S or α6β2γ2S receptors were compared during continuous bath application of MeHg. A time-dependent increase in IGABA mediated by both receptor subtypes occurred following the first 25–30 min of MeHg (5 μM) exposure. In α6β2γ2S containing receptors, the MeHg-induced increase in IGABA was less pronounced compared to that mediated by α1β2γ2S containing 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 IGABA rapidly and completely reversed the MeHg-induced currents. Therefore these MeHg-increased inward currents are mediated specifically by the two subtypes of GABAA receptors 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 IGABA in oocytes expressing either α1β2γ2S or α6β2γ2S receptors prior to its more defined later effects, suggesting that MeHg may initially interact directly with GABAA receptors in a reversible manner to cause this potentiation.

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