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

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，在脑和脊髓内的快速突触神经传递中起重要作用，并且是神经系统复杂行为的基础，但当功能失调时可能导致严重的神经系统问题。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（过度增生）的发生是因为点突变损害了甘氨酸受体（GlyR）的渗透和激活。类似地，现在已知某些癫痫是由兴奋性乙酰胆碱受体（achr）通道区域的突变或附近突变引起的，这些突变影响通道激活和离子渗透。然而，由于它们具有非常显著的结构和功能相似性，从llic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应用潜力，而结构更简单的GlyR具有一定的研究优势。该项目的第一个目标是研究这些离子通道的分子生物学结构是如何控制渗透的，它是如何影响不同的离子如何选择性地通过它，以及它是如何影响通道激活的。第二个相关目标是更多地了解GlyR受体的脱敏过程，即高浓度激动剂的持续存在可导致受体反应的减少。第三个目的是专门研究两种新的惊吓疾病突变导致的分子破坏模式的机制，除了它们自身固有的临床价值外，还可以提供有关受体功能的一般信息。

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.