Structural determinants underlying high conductance GABA-A channels

被称为GABA-A受体的大型蛋白质广泛分布在大脑各处，是大多数神经元受到抑制的原因。许多全身麻醉剂、镇静剂和抗癫痫药物通过调节GABA-A受体发挥作用。如果没有全身麻醉剂使患者失去知觉，现代手术是不可能的，但这些有价值的药物仍然有不想要的副作用。例如，它们中的一些会影响心脏和呼吸功能。仍然需要新的、更有效的全身麻醉剂。在欧洲和北美，每200人中就有一人患有癫痫，3%的人口患有焦虑症。目前使用的主要全身麻醉剂，抗焦虑和抗癫痫药物，作用于大脑中的GABA-A受体。据估计，这些药物的潜在年市场规模为27亿美元。1999年麻醉剂的世界市场价值为16亿美元。所有这些都是偶然发现的。如果了解了这些药物的分子位置和作用方式，就有可能发现新的、更具选择性的药物。从这个项目中获得的关于GABA-A受体的信息有望有助于理解这些受体是如何工作的，并有助于开发作用于GABA-A受体的新一代药物。在这个项目中，我们计划检查功能后果是什么，以及GABA-A受体如何在膜上共定位，类似于它们在大脑中的物理状态。我们将检查药物对共定位在膜上的受体的影响。我们有初步证据表明，当GABA-A受体彼此靠近时，它们会一起打开，从而使它们的抑制反应最大化。药物也能使GABA-A受体协同开放。膜上的受体相互交谈的概念已经被证明存在于来自不同类别的受体，但我们现在有证据表明，相同类型的受体，即GABA-A受体，能够相互交谈。

Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. The leading general anaesthetics, anxiolytic and anti-epileptic drugs currently used, act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered by serendipity. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. In this project we plan to examine what the functional consequences are and how GABA-A receptors colocalise in the membrane, akin to their physical state in the brain. We will examine the effects of drugs on receptors colocalised in the membrane. We have preliminary evidence suggesting that when GABA-A receptors are close to each other they open together so that their inhibitory response is maximised. Drugs are also able to make GABA-A receptors open in concert. The concept that receptors in the membrane talk to each other has been shown to occur for receptors from different classes but we now have evidence that the same type of receptors i.e. GABA-A receptors, are able to talk to each other.