Effects of mutations in the conserved cysteine loop of the GABA-A receptor

抑制大脑中的兴奋信号是一种叫做GABA-A受体的大蛋白质的功能。许多全身麻醉剂、镇静剂和抗癫痫药物通过调节GABA-A受体起作用。如果不使用全身麻醉剂使病人失去知觉，现代外科手术是不可能的。然而，这些有价值的药物仍然会产生不必要的副作用：例如，其中一些药物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%的人患有焦虑症。目前使用的主要全身麻醉药、抗焦虑药和抗癫痫药作用于大脑中的GABA-A受体。这些药物的潜在年市场估计为27亿美元。1999年世界麻醉剂市场为16亿美元。都是偶然发现的。如果这些药物的分子位点和作用模式被理解，就有可能发现新的、更具选择性的药物。在这个项目中获得的关于GABA-A受体的信息预计将有助于了解这些受体如何工作，并开发新一代作用于GABA-A受体的药物。GABA-A受体的特定突变可能对其功能产生深远影响。研究突变的影响正在慢慢地为我们提供更多关于离子通道区域和药物结合位点的信息。最近，已发现GABA-A受体的突变与某些形式的癫痫有关。在这个项目中，我们计划研究GABAA受体亚基的一个小区域的高度保守残基突变的影响，因为：（1）我们（和其他人）有初步证据表明，这个环形成了GABA结合位点和离子通道之间的连接，（2）我们认为受体的这一部分对某些药物的作用至关重要。

Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. 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. However, these valuable drugs can still have unwanted side effects: for example, some of them can 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. Leading, currently used general anaesthetics, anxiolytic and anti-epileptic drugs 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 serendipitously. 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. Specific mutations in GABA-A receptors can have a profound influence on their function. Studying the effects of mutations is slowly giving us more information about the ion channel region and drug binding sites. Recently, mutations in GABA-A receptors have been found to be associated with some forms of epilepsy. In this project, we plan to examine the effects of mutations in highly conserved residues of a small region of subunits of the GABAA receptor because: (1) we (and others) have preliminary evidence that this loop forms a connection between the GABA binding site and the ion channel and (2) we think that this part of the receptor is vital for the effects of some drugs.