(Kumar et al. 2003). GABAA receptor β2 and/or γ2 subunits are required for recognition of the receptor by the AP-2 that precedes clathrin-dependent endocytosis (Herring et al. 2003; Kittler et al. 2005, 2008). Therefore, it is possible that PKC-mediated phosphorylation of GABAA receptor subunits, receptor-associated proteins, and/or AP-2 following chronic ethanol administration alters the recognition and endocytosis of GABAA receptors. Indeed, chronic ethanol consumption results in increased expression of α4-, β2-, and β3-GABAA receptor subunits in the cerebral cortex and all of these subunits contain consensus phosphorylation sites for PKC (Macdonald 1995; Mohler et al. 1996; Wisden et al. 1991). In contrast, α1-, α2-, and α3-GABAA receptor subunits are decreased in the cortex and these subunits do not contain consensus phosphorylation sites for PKC. Hence, it is likely that phosphorylation of GABAA receptor subunits can prevent internalization by blocking AP-2 binding. A recent study has shown that a single dose of ethanol can increase the internalization of GABAA receptor α4 and δ subunits (Liang et al. 2007). However, this study did not investigate the mechanism of GABAA receptor internalization. Therefore, investigation of GABAA receptor endocytosis and trafficking following ethanol exposure is essential for understanding the mechanisms of ethanol adaptations.
