Methylmercury Induces An Initial Increase In Gaba-Evoked Currents In Xenopus Oocytes Expressing Alpha(1) And Alpha(6) Subunit-Containing Gaba(A) Receptors

Early onset effects of methylmercury (MeHg) on recombinant alpha(1)beta(2)gamma(2s) or alpha(6)beta(2)gamma(2s) subunit-containing GABA(A) 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 I-GABA in Xenopus laevis oocytes expressing either alpha(1)beta(2)gamma(2s) or alpha(6)beta(2)gamma(2s) receptors were compared during continuous bath application of MeHg. A time-dependent increase in I-GABA mediated by both receptor subtypes occurred following the first 25-30 min of MeHg (5 mu M) exposure. In alpha(6)beta(2)gamma(2s) containing receptors, the MeHg-induced increase in I-GABA was less pronounced compared to that mediated by alpha(1)beta(2)gamma(2s) 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 I-GABA rapidly and completely reversed the MeHg-induced currents. Therefore these MeHg-increased inward currents are mediated specifically by the two subtypes of GABA(A) 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 I-GABA in oocytes expressing either alpha(1)beta(2)gamma(2s) or alpha(6)beta(2)gamma(2s) receptors prior to its more defined later effects, suggesting that MeHg may initially interact directly with GABA(A) receptors in a reversible manner to cause this potentiation. (C) 2016 Published by Elsevier B.V.