Macdonald R L, Twyman R E, Ryan-Jastrow T, Angelotti T P
Department of Neurology, University of Michigan Medical Center, Ann Arbor.
Epilepsy Res Suppl. 1992;9:265-77.
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.
GABAA受体通道是一种受到高度调节的受体。该受体的功能可能会被改变GABA结合速率、改变通道门控或阻断通道的药物所修饰。受体亚基的磷酸化也可能会改变受体的生物物理特性、稳定性或组装。虽然GABA能抑制在调节神经元兴奋性中起主要作用，但GABA能抑制改变在癫痫发病机制中的作用仍有待证实。GABAA受体由多个亚基组成，并且不同亚基组合的GABAA受体的特性和药理学不同，这表明GABAA受体的异质性可能在决定神经系统不同区域GABA能抑制的特性方面具有重要意义。虽然很明显神经系统中存在GABAA受体异质性，但受体异质性在癫痫发病机制中的作用仍不确定。GABAA受体异质性可能对癫痫治疗有影响。由于表达对变构调节剂敏感性不同的亚基的受体，调节GABA能功能的药物在神经系统的不同区域可能具有不同的疗效。此外，GABAA受体的化学计量或亚基组成可能存在发育变化，使发育中的神经系统对GABA能抗惊厥药物的作用或多或少敏感。除了GABAA受体的异质性表达外，其他有关GABA能功能调节的问题也具有潜在重要性。控制特定受体亚型表达和GABA受体水平的调节事件尚不清楚。调节GABAA受体功能的翻译后事件也不确定。GABAA受体通过磷酸化进行的翻译后调节可能导致癫痫中GABAA受体功能改变。要了解GABAA受体异质性在癫痫发病机制中的作用，需要结合生物物理和分子生物学技术。不仅要确定GABAA受体的特性在特定形式的癫痫中是否发生改变，还要确定基因表达是否发生改变，这将是很重要的。
