Structure-function studies of ion permeation and selectivity in recombinant glycine receptor channels

重组甘氨酸受体通道离子渗透和选择性的结构功能研究

• 批准号: nhmrc : 222830
• 负责人: A/Pr Andrew Moorhouse
• 金额: $ 22.09万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structure-function-studies-receptor-channels/98829
• 关键词: Structure; function; studies; ion; permeation

Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.

配体门控离子通道（LGIC）是受体通道超家族的成员，具有非常显著的结构和功能相似性，其在脑和脊髓内的快速突触神经传递中起主要作用，并且是神经系统的复杂行为的基础，但是当功能障碍时可导致重大神经问题。甘氨酸是中枢神经系统中两种最重要的抑制性神经递质之一。受损的甘氨酸介导的神经传递是一系列遗传性神经系统疾病的基础，并且已经表明，人类疾病家族性惊吓病（hyperekplexia）的发生是由于损害甘氨酸受体（GlyR）的渗透和活化的点突变。类似地，现在已知某些癫痫是由兴奋性乙酰胆碱受体（AChR）中的通道区域中或附近的突变引起的，其影响通道激活和离子渗透。然而，由于它们非常显著的结构和功能相似性，在LGIC受体家族的一个成员中获得的信息对其他成员具有很强的潜在应用，并且具有更简单结构的GlyR具有一定的研究优势。该项目的第一个目的是研究这些离子通道的分子生物学结构如何控制渗透，它如何影响不同离子选择性地通过它，以及它如何影响通道激活。第二个相关的目的是了解更多关于GlyR受体脱敏的过程，其中高浓度激动剂的持续存在可导致受体反应的降低。第三个目的是专门调查的分子破坏模式的机制，导致两个新的惊吓疾病突变，其中，除了自己固有的临床价值，也可以给受体功能的一般信息。