Post-translational modifications such as phosphorylation and glycosylation of GABAA receptors may play a role in the development of EtOH-dependence. In particular, phosphorylation of GABAA receptors has been demonstrated to modulate receptor function. In Xenopus oocytes and isolated mouse brain membrane vesicles (microsacs), PKC and PKA phosphorylation of GABAA receptors decreases receptor activation (Kellenberger et al. 1992; Krishek et al. 1994; Leidenheimer et al. 1992). Phosphorylation by CAM kinase II or tyrosine kinase enhances GABAA receptor function (Churn et al. 2002; Valenzuela et al. 1995). As discussed previously, acute EtOH induces changes in GABAA receptor function that may be dependent on phosphorylation of particular proteins. Chronic EtOH exposure might be expected to result in long-term changes in second messenger systems, including kinase activity. However, the heterogeneity of GABAA receptors expressed in vivo has precluded definitively answering this question and none of these studies have directly demonstrated that phosphorylation is involved in EtOH modulation of GABAA receptor function. The exact mechanisms involved in the alteration of GABAA receptor function following chronic EtOH exposure still remain to be determined.
