Epression of Ion Channels in the Auditory System

描述（由申请人提供）：听觉脑干神经元以非常高的速率和非常高的时间精度放电，使它们能够编码声音刺激的特定特征。出乎意料的是，已经发现这些神经元中钾通道的水平和特征被听觉环境迅速改变。我们计划确定两类K+通道的这种使用依赖性可塑性的机制，i）电压依赖性Kv3.1b通道和ii）由Slack和Slick基因编码的Na+激活的K+通道（KNa通道）。Kv3.1b通道的功能是允许神经元以高频率放电。我们计划确定声音诱导的Kv3.1b蛋白水平的增加是否导致质膜中更高的Kv3.1b电流并增强MNTB神经元以更高速率放电的能力。我们还计划测试的假设，KNa电流的幅度是由声音引起的磷酸化状态的变化，以提高这些神经元在高速率的刺激时间的准确性。对于Kv3.1b和KNa通道，我们将确定电流的活性依赖性增加是否受到脆性X智力迟钝蛋白（FMRP）的调节，FMRP是一种结合Kv3.1 mRNA并通过直接蛋白质-蛋白质相互作用调节KNa通道的蛋白质翻译阻遏物。了解听觉神经元的兴奋性如何受生理刺激调节，可能会导致新的药物治疗听觉功能障碍，包括耳鸣，年龄相关性听力损失和听源性癫痫发作，以及脆性X综合征和其他兴奋性障碍。 公共卫生相关性：最近的证据表明，大脑内的听觉神经元的兴奋性迅速修改周围声环境的变化。该提案中的实验将确定调整这些神经元中离子通道特性的生化和生物机制，使它们能够在嘈杂的环境中保持高精度。该信息将用于确定哪类药理学试剂可用于治疗听觉功能障碍，包括耳鸣、年龄相关性听力损失和听源性癫痫发作以及脆性X综合征。

DESCRIPTION (provided by applicant): Auditory brainstem neurons fire at very high rates with extraordinarily high temporal precision, allowing them to encode specific features of sound stimuli. Unexpectedly, it has been found that the levels and characteristics of potassium channels in these neurons are rapidly modified by the auditory environment. We plan to determine the mechanisms of this use-dependent plasticity for two classes of K+ channels, i) voltage-dependent Kv3.1b channels and ii) Na+-activated K+ channels (KNa channels) encoded by the Slack and Slick genes. The function of Kv3.1b channels is to allow neurons to fire at high frequencies. We plan to determine whether sound- induced increases in Kv3.1b protein levels result in higher Kv3.1b currents in the plasma membrane and enhance the ability of MNTB neurons to fire at higher rates. We also plan to test the hypothesis that KNa current amplitude is regulated by sound-induced changes in phosphorylation state to enhance the temporal accuracy of these neurons at high rates of stimulation. For both Kv3.1b and KNa channels we will determine whether the activity-dependent increases in current are regulated by the Fragile X Mental Retardation Protein (FMRP), a repressor of protein translation that binds Kv3.1 mRNA and that modulates KNa channels by direct protein- protein interactions. An understanding of how the excitability of auditory neurons is regulated by physiological stimuli is likely to lead to novel pharmacological treatments for disorders of auditory function including tinnitus, age-related hearing loss and audiogenic seizures, as well as Fragile X syndrome and other disorders of excitability. PUBLIC HEALTH RELEVANCE: Recent evidence has shown that the excitability of auditory neurons within the brain is rapidly modified by changes in the ambient acoustic environment. The experiments in this proposal will determine the biochemical and biological mechanisms that adjust the properties of ion channels in these neurons, allowing them to maintain high accuracy in noisy environments. This information will be used to determine which classes of pharmacological agents can be used for the treatment of disorders of auditory function including tinnitus, age- related hearing loss and audiogenic seizures, as well as Fragile X syndrome.