Regulation of GTBAA receptor channels anticonvulsant and convulsant drugs and by phosphorylation

Department of Neurology, University of Michigan Medical Center, Ann Arbor.
Epilepsy research. Supplement 02/1992; 9:265-77.
Source: PubMed


The GABAA receptor channel is a highly regulated receptor. The function of the receptor may be modified by drugs which alter the rates of binding of GABA, modify the gating of the channel or block the channel. It is also likely that phosphorylation of the receptor subunits modifies the biophysical properties, stability or assembly of the receptor. While GABAergic inhibition plays a major role in the regulation of neuronal excitability, a role for altered GABAergic inhibition in the pathogenesis of epilepsy remains to be proven. The demonstration that GABAA receptors are composed of multiple subunits and that the properties and pharmacology of GABAA receptors are different for different subunit combinations suggests that GABAA receptor heterogeneity may be of importance in determining the properties of GABAergic inhibition in different regions of the nervous system. While it is clear that GABAA receptor heterogeneity is present in the nervous system, a role for receptor heterogeneity in the pathogenesis of epilepsy remains uncertain. GABAA receptor heterogeneity may have implications for the treatment of epilepsy. It is quite possible that drugs which regulate GABAergic function may have variable efficacy in different regions of the nervous system due to expression of receptors with subunits that have different sensitivity to allosteric regulators. Furthermore, it is likely that there are developmental changes in the stoichiometry or subunit composition of GABAA receptors rendering the developing nervous system more or less sensitive to the effects of GABAergic anticonvulsant drugs. In addition to the heterogeneous expression of GABAA receptors, other issues concerning the regulation of GABAergic function are of potential importance. The regulatory events that control the expression of specific receptor subtypes and levels of GABA receptors are unknown. The post-translational events that regulate GABAA receptor function are uncertain. It is possible that post-translational regulation of GABAA receptors by phosphorylation may contribute to altered GABAA receptor function in epilepsy. To understand the role of GABAA receptor heterogeneity in the pathogenesis of epilepsy will require the combination of biophysical and molecular biological techniques. It will be important to determine not only whether the properties of GABAA receptors have been altered in a specific form of epilepsy, but also whether gene expression has been altered.

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    • "Because diazepam exerts its anticonvulsant effect primarily by enhancing GABAergic inhibition by acting on GABARs (Macdonald et al., 1992), we hypothesized that seizures altered the functional properties of GABARs. The seizures could potentially alter the modulation of GABAR by various drugs, such as enhancement by benzodiazepines, barbiturates, and neurosteroids and antagonism by penicillin, picrotoxin, bicuculline, and Zn 2+ . "
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