Extrasynaptic alpha4 GABAA receptors contribute to the molecular mechanism of ethanol action. Ethanol administration has been shown to alter expression of alpha4 GABAA receptors in a spatial and temporal manner, which may contribute to ethanol's neuroadaptive mechanisms. However, the exact cellular mechanism of alpha4 GABAA receptor regulation remains unclear. GABAA alpha4 receptor subunits contain PKC phosphorylation consensus sites. In the current study, we assessed the effects of ethanol on thalamic GABAA receptor alpha4 subunits and PKC isozymes in vivo following 3.5 g/kg i.p. ethanol administration. Thalamic alpha4 subunit levels were found to be temporally regulated following acute ethanol administration, with a 27% decrease observed at 2hrs, followed by a 25% increase at 4 hrs. PKC isozymes were also differentially regulated following ethanol administration. PKCgamma and PKCdelta were decreased ~25-30% following ethanol exposure (2 hrs), while no changes were observed in PKCbeta or PKCepsilon isozymes. Additionally, there was an ~60% decrease in the abundance of serine phosphorylated alpha4 subunits in the P2 fraction. Neither administration of the 5alpha-reductase inhibitor finasteride or flumazenil altered ethanol-induced changes in alpha4 expression at this time point. Overall, these studies suggest that thalamic alpha4 GABAA receptors as well as PKC isozymes are temporally regulated following ethanol administration. These effects may contribute to rapid ethanol tolerance. Supported by NIAAA.
Ethanol-induced temporal regulation of thalamic GABAA receptor alpha4 subunits is associated with changes in PKCgamma and PKCdelta expression
Porcu P;
2009
Abstract
Extrasynaptic alpha4 GABAA receptors contribute to the molecular mechanism of ethanol action. Ethanol administration has been shown to alter expression of alpha4 GABAA receptors in a spatial and temporal manner, which may contribute to ethanol's neuroadaptive mechanisms. However, the exact cellular mechanism of alpha4 GABAA receptor regulation remains unclear. GABAA alpha4 receptor subunits contain PKC phosphorylation consensus sites. In the current study, we assessed the effects of ethanol on thalamic GABAA receptor alpha4 subunits and PKC isozymes in vivo following 3.5 g/kg i.p. ethanol administration. Thalamic alpha4 subunit levels were found to be temporally regulated following acute ethanol administration, with a 27% decrease observed at 2hrs, followed by a 25% increase at 4 hrs. PKC isozymes were also differentially regulated following ethanol administration. PKCgamma and PKCdelta were decreased ~25-30% following ethanol exposure (2 hrs), while no changes were observed in PKCbeta or PKCepsilon isozymes. Additionally, there was an ~60% decrease in the abundance of serine phosphorylated alpha4 subunits in the P2 fraction. Neither administration of the 5alpha-reductase inhibitor finasteride or flumazenil altered ethanol-induced changes in alpha4 expression at this time point. Overall, these studies suggest that thalamic alpha4 GABAA receptors as well as PKC isozymes are temporally regulated following ethanol administration. These effects may contribute to rapid ethanol tolerance. Supported by NIAAA.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
