Birnir Bryndis, Korpi Esa R
Lund University, School of Medicine, CRC, Entry 72, house 91, level 11, UMAS, 205 02 Malmo, Sweden.
Curr Pharm Des. 2007;13(31):3169-77. doi: 10.2174/138161207782341330.
Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
大多数关于GABA(A)受体辅助蛋白的研究都集中在形成通道的亚基的转运、聚集和磷酸化状态上，因此已经确定了许多能够影响GABA(A)通道在细胞质膜中的表达和功能的蛋白质和机制。鉴于越来越多的细胞内和跨膜神经元蛋白被证明会影响神经元中GABA(A)受体的命运、功能和药理学特性，构成天然GABA(A)受体复合物的概念可能需要重新审视。或许更合适的做法是将相关蛋白或其中一些蛋白视为受体通道复合物的一部分，作为辅助蛋白发挥作用。在此，我们重点介绍细胞内环境对GABA激活通道功能和药理学的一些影响。这些研究表明，在异源表达系统中，辅助蛋白需要与GABA(A)通道形成亚基共表达，才能获得在天然神经元环境中记录到的GABA(A)受体的全部特征。对于大多数辅助蛋白而言，还需要进一步开展研究，例如在基因修饰动物模型上进行研究，以确定它们在正常生理学以及神经和精神疾病病理生理学中的意义。阐明辅助蛋白和相关过程（如磷酸化）以及亚细胞定位对GABA(A)受体通道功能和药理学特性“微调”的影响，仍然是一项挑战。
