Structural determinants underlying high conductance GABA-A channels

高电导 GABA-A 通道的结构决定因素

• 批准号: nhmrc : 418027
• 负责人: Dr Mary Louise Tierney
• 金额: $ 24.28万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structural-determinants-underlying-a-channels/81766
• 关键词: Structural; determinants; underlying; conductance; GABA

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.

广泛分布于整个大脑的称为 GABA-A 受体的大蛋白负责抑制大多数神经元。许多全身麻醉药、镇静剂和抗癫痫药通过调节 GABA-A 受体发挥作用。如果不使用全身麻醉使患者失去知觉，现代手术就不可能实现，但这些有价值的药物仍然有不良副作用。例如，其中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 1 人患有癫痫症，3% 的人口患有焦虑症。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年世界麻醉药市场规模为16亿美元。一切都是偶然发现的。如果了解这些药物的分子位点和作用方式，就有可能发现新的、更具选择性的药物。该项目中获得的有关 GABA-A 受体的信息预计将有助于了解这些受体的工作原理以及开发作用于 GABA-A 受体的新一代药物。在这个项目中，我们计划研究功能后果是什么，以及 GABA-A 受体如何在膜中共定位，类似于它们在大脑中的物理状态。我们将检查药物对膜上共定位受体的影响。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。药物还能够使 GABA-A 受体协同开放。膜上的受体可以相互交谈的概念已被证明适用于不同类别的受体，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。