knockout mice show reduced sensitivity to the anxiolytic effects of both intoxicating and sedative doses of ethanol (Bowers et al. 2001), while PKCδ knockout mice are insensitive to the ataxic effects of ethanol (Choi et al. 2008) and PKCε knockout mice show increased ethanol sensitivity (Hodge et al. 1999). Furthermore, mice lacking the gene for PKCγ show a significant reduction in ethanol potentiation of GABA responses compared to responses in wildtype mice (Harris et al. 1995; Proctor et al. 2003). In contrast, ethanol and flunitrazepam potentiation of muscimol-stimulated chloride (Cl−) uptake is greater in microsacs from PKCε knockout mice compared to wildtype controls (Hodge et al. 1999). Therefore, it appears that the ε and γ isoforms of PKC have opposing influences on ethanol enhancement of GABAA receptor function. PKCδ plays a critical role in ethanol effects on extrasynaptic GABAA receptors. PKCδ knockout mice display a reduction in ethanol-induced ataxia as well as ethanol-mediated tonic current in thalamic and dentate granule cell neurons (Choi et al. 2008). Taken together, it is likely that various PKC isoforms mediate phosphorylation of GABAA receptors and/or associated proteins and modulate GABAA receptor function following ethanol exposure.
