Role of presynaptic Kv3 potassium channel subunits in forming native potassium channels and adapting synaptic transmission and auditory processing

这项提议是莱斯特大学的突触和离子通道生理学家与伦敦和维罗纳的Autifony Therapeutics药理学家之间的培训合作。目的是测试已知可改变Kv 3钾通道门控和活性的新型化合物。这些动作影响神经元的兴奋性，其中Kv 3通道在复极化动作电位中充当延迟整流器。这些化合物是耳鸣和其他过度兴奋性疾病的潜在治疗剂。据推测，几种化合物对四种Kv 3亚基中的一些具有不同的作用（每个亚基由不同的基因kcnc 1 -4指定）。事实上，异聚体通道通常在不同的神经元位置被运输和表达，因此提供了特定先导化合物在脑的特定区域中的差异作用的可能性。在听觉脑干中，只有Kv3.1和Kv3.3表达，但Kv3.1在内侧核中的比例更大，而Kv3.3在外侧核中占主导地位，因此我们可以利用这一点来测试不同亚基组成的天然Kv 3通道上的先导化合物（并且我们可以通过使用缺乏一种或其他亚基的转基因敲除小鼠来修改该组成）。Kv3.3亚基也与突触前末梢有关;由于我们可以从Held巨突触的萼进行突触前记录，我们可以检验这些药物可能具有不同的突触前和突触后效应的假设。因此，该项目将为Kv 3通道亚基的分布和功能提供重要的见解，并为Autifony提供其先导化合物作用于神经元兴奋性和突触传递的机制的详细知识，并建议进一步完善药理学。

This proposal is a training collaboration between synaptic and ion channel physiologists at the University of Leicester and Autifony Therapeutics pharmacologists based in London and Verona. The aim is to test novel compounds known to modify the gating and activity of Kv3 potassium channels. These actions influence the excitability of neurons, where Kv3 channels act as delayed rectifiers in repolarizing action potentials. The compounds are potential therapeutic agents for tinnitus and other hyperexcitability disorders. It is suspected that several of the compounds have differential actions on some of the four Kv3 subunits (each specified by a different gene, kcnc1-4). Indeed heteromeric channels are commonly trafficked and expressed in differing neuronal locations, so giving the possibility of differential action of specific lead compounds in particular areas of the brain. In the auditory brainstem only Kv3.1 and Kv3.3 are expressed, but the proportion of Kv3.1 is greater in medial nuclei while Kv3.3 dominates in lateral nuclei, so we can exploit this to test the lead compounds on native Kv3 channels of differing subunit composition (and we can modify that composition by using transgenic knockout mice which lack one or other subunit). Kv3.3 subunits are also associated with presynaptic terminals; since we can conduct presynaptic recordings from the calyx of Held giant synapse, we can test the hypothesis that these drugs may have different pre- and post-synaptic effects. So this project will provide important insights into the distribution and function of Kv3 channel subunits and provide Autifony with detailed knowledge of the mechanisms by which their lead compounds act on neuronal excitability and synaptic transmission and suggest further refinement of the pharmacology.