Regulation of Kv3.1 by MiRPs in Auditory Neurons

听觉神经元中 MiRP 对 Kv3.1 的调节

• 批准号: 6839836
• 负责人: Geoffrey W Abbott
• 金额: $ 8.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839836
• 关键词: acoustic nerve; auditory feedback; auditory stimulus; biological models; dynamin; genetic regulation; genetically modified animals; immunocytochemistry; laboratory mouse; potassium channel; protein protein interaction; protein structure function; sectioning

DESCRIPTION (provided by applicant): Ion channels underlie the rapid and diverse electrical signaling in neurons that enables complex organisms to sense and react to their environment, move, learn, communicate and problem-solve in a highly sophisticated manner. The diverse range of voltage-gated potassium (Kv) currents expressed in the brain is essential for signal processing and integration in neuronal circuits. High frequency, temporally precise firing in auditory neurons requires potassium channels formed by Kv3.1, characterized by rapid gating and activation at relatively depolarized potentials. Auditory neurons of Kv3.1 knockout mice are unable to follow high frequency stimulation, a model for hearing loss in the high-frequency range in humans. Dynamic regulation of Kv3.1 current properties is thought to modulate the firing frequency of auditory neurons in response to different stimulus frequencies. We recently found that Kv3.1 forms complexes with MiRP2, a single transmembrane domain channel ancillary subunit, in mammalian brain. Further, MiRP2 and related subunits MinK and MiRP1 modify Kv3.1 gating properties, slowing their activation and deactivation and altering voltage dependence, current density and inactivation. We now propose to investigate whether MiRPs can associate with Kv3.1 channels in auditory neurons, whether MiRPs regulate Kv3.1 trafficking, and which aspects of Kv3.1 regulation by MiRPs could underlie Kv3.1 current heterogeneity in auditory neurons, and thus wide-frequency auditory perception. Our Specific Aims are: 1. Determine the ability of MinK, MiRP1 and MiRP2 to form complexes with Kv3.1 alpha subunits in auditory neurons. 2. Determine the ability of MinK, MiRP1 and MiRP2 to mediate dynamin-dependent internalization of Kv3.1 alpha subunits. 3. Examine the predicted effects in auditory neurons of MiRP modulation of Kv3.1, Kv3.3 and Kv3.1-Kv3.3 channels using a combination of heterologous coexpression experiments and computer simulations.

描述（由申请人提供）：离子通道是神经元中快速多样的电信号传导的基础，使复杂的生物体能够感知环境并对其做出反应，以高度复杂的方式移动、学习、交流和解决问题。大脑中表达的不同范围的电压门控钾 (Kv) 电流对于神经元回路中的信号处理和整合至关重要。听觉神经元的高频、时间精确放电需要 Kv3.1 形成的钾通道，其特点是在相对去极化电位下快速门控和激活。 Kv3.1 敲除小鼠的听觉神经元无法跟随高频刺激，这是人类高频范围听力损失的模型。 Kv3.1 电流特性的动态调节被认为可以调节听觉神经元响应不同刺激频率的放电频率。我们最近发现 Kv3.1 在哺乳动物大脑中与 MiRP2（一种单跨膜域通道辅助亚基）形成复合物。此外，MiRP2 和相关亚基 MinK 和 MiRP1 修改 Kv3.1 门控特性，减缓其激活和失活，并改变电压依赖性、电流密度和失活。我们现在建议研究 MiRP 是否可以与听觉神经元中的 Kv3.1 通道相关联，MiRP 是否调节 Kv3.1 运输，以及 MiRP 调节 Kv3.1 的哪些方面可能是听觉神经元中 Kv3.1 当前异质性的基础，从而导致宽频听觉感知。 我们的具体目标是： 1. 确定 MinK、MiRP1 和 MiRP2 与听觉神经元中的 Kv3.1 α 亚基形成复合物的能力。 2. 确定 MinK、MiRP1 和 MiRP2 介导 Kv3.1 α 亚基的动力依赖性内化的能力。 3. 结合异源共表达实验和计算机模拟，检查 Kv3.1、Kv3.3 和 Kv3.1-Kv3.3 通道的 MiRP 调制对听觉神经元的预测效果。