Epression of Ion Channels in the Auditory System

听觉系统中离子通道的抑制

• 批准号: 8444258
• 负责人: LEONARD K KACZMAREK
• 金额: $ 33.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444258
• 关键词: Acoustic Stimulation; Acoustics; Action Potentials; Animals; Auditory; Auditory system; Binding; Binding Proteins; Biochemical; Biological; Brain; Brain Stem; Cell Nucleus; Cell membrane; Characteristics; Consensus; Disease; Environment; Fire - disasters; Fragile X Mental Retardation Protein; Fragile X Syndrome; Frequencies; Generations; Genes; Genetic Transcription; Grant; In Vitro; Ion Channel; Kinetics; Lead; Liquid Chromatography; Medial; Messenger RNA; Neurons; Pattern; Pharmacological Treatment; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Physiological; Plastics; Potassium Channel; Preparation; Presbycusis; Property; Protein Binding; Protein Dephosphorylation; Protein Kinase C; Protein phosphatase; Proteins; Repressor Proteins; Research Support; Site; Site-Directed Mutagenesis; Slice; Staining method; Stains; Stimulus; Synapses; Testing; Tinnitus; Translations; Wild Type Mouse; audiogenic seizure; auditory pathway; improved; in vivo; inhibitor/antagonist; knockout animal; novel; protein protein interaction; public health relevance; reconstitution; research study; response; sound; tandem mass spectrometry; trapezoid body; voltage

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.

描述（由申请人提供）：听觉脑干神经元以非常高的时间精度发射非常高的速度，从而可以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是通过听觉环境迅速改变的。我们计划确定两类K+通道的使用依赖性可塑性的机制，i）依赖电压的Kv3.1B通道和II）Na+活化的K+通道（KNA通道），由松弛和光滑基因编码。 KV3.1B通道的功能是允许神经元以高频发射。我们计划确定声音诱导的Kv3.1b蛋白水平是否会导致质膜中的Kv3.1b电流较高，并增强MNTB神经元以更高速率发射的能力。我们还计划测试以下假设：KNA电流幅度受声诱导的磷酸化状态变化的调节，以提高这些神经元的时间准确性，以高刺激速率。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脆弱的X智力低下蛋白（FMRP）调节，X智力低下蛋白（FMRP）是蛋白质翻译的阻遏物，该蛋白质翻译结合Kv3.1 mRNA并通过直接蛋白质蛋白质相互作用调节KNA KNA通道。了解听觉神经元的兴奋性如何受到生理刺激的调节，可能会导致对听觉功能疾病（包括耳鸣，与年龄相关的听力损失和听觉性癫痫发作）以及脆弱的X综合征和其他兴奋性疾病的新型药理治疗。