ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS

离子通道和激发模式的乙酰胆碱调节

• 批准号: 6302882
• 负责人: BRUCE P BEAN
• 金额: $ 19.78万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302882
• 关键词: Rana; acetylcholine; action potentials; calcium channel; calcium channel blockers; hippocampus; laboratory mouse; laboratory rat; muscarinic receptor; neural transmission; neurons; neuropharmacology; sodium channel; sympathetic nervous system; tissue /cell culture; voltage /patch clamp; voltage gated channel

Acetylcholine acting through muscarinic receptors modulates the excitability of neurons by altering various sodium, calcium, and potassium channels. This modulation of excitability plays a central role in cholinergic regulation of wakefulness, cognition, and memory. The goal of the proposed research is to understand muscarinic changes in action potential formation and firing patterns in terms of modulation of particular ion channels. Patch clamp techniques will be used to study the control of sodium, potassium, calcium channels in sympathetic, hippocampal, and dopamine neurons by muscarinic stimulation. The primary experimental preparation will be acutely isolated neurons, which allow voltage-clamp with sufficient speed to characterize modulation of the large, rapid currents flowing during action potentials. This will extend previous work using brain slices, in which only relatively small and slow currents could be studied under voltage-clamp. We will directly examine currents flowing during action potentials by first recording action potential wave-forms and, in the same cell, using those wave forms as command voltages in voltage clamp experiments. By using pharmacological tools to separate individual current sand performing both current-clamp and voltage-clamp experiments in the presence of acetylcholine, it should be possible to determine the role of modulation of particular channel types in contribution to overall changes in excitability. Muscarinic control of ion channels and neuronal excitability is a basic process for the normal operation of the brain, and evidence suggests changes in the aging brain. Changes in muscarinic modulation of hippocampal neurons may be centrally involved in the symptoms of Alzheimer's disease, and better understanding of the channels involved may lead to novel therapeutic interventions, for example by using ion channel blockers to mimic effects of acetylcholine.

乙酰胆碱通过毒蕈碱受体发挥作用，调节 通过改变各种钠、钙和钾来提高神经元的兴奋性 渠道。这种兴奋性的调节在 胆碱能调节觉醒、认知和记忆。目标是 拟议的研究是为了了解毒蕈碱的作用变化 调制方面的潜在形成和激发模式 特定的离子通道。膜片钳技术将用于研究 控制交感神经中的钠、钾、钙通道， 海马和多巴胺神经元受到毒蕈碱刺激。初级 实验准备将是急剧分离的神经元，这使得 电压钳位具有足够的速度来表征调制 动作电位期间有大而快速的电流流动。这将延长 之前的工作使用大脑切片，其中只有相对较小且缓慢的 可以在电压钳下研究电流。我们将直接检查 通过首先记录动作在动作电位期间流动的电流 潜在的波形，并在同一单元中，使用这些波形作为 电压钳实验中的命令电压。通过使用药理 用于分离单个电流沙的工具，同时执行电流钳 和电压钳实验在乙酰胆碱存在的情况下，它应该 可以确定特定通道的调制作用 类型对兴奋性整体变化的贡献。毒蕈碱 离子通道和神经元兴奋性的控制是 大脑的正常运作，有证据表明 老化的大脑。海马神经元毒蕈碱调节的变化可能 集中参与阿尔茨海默病的症状，并且更好 了解所涉及的通道可能会带来新的治疗方法 干预措施，例如使用离子通道阻滞剂来模拟效果 乙酰胆碱。