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: 6410666
• 负责人: BRUCE P BEAN
• 金额: $ 29.59万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410666
• 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.

通过毒蕈碱受体作用的乙酰胆碱可调节 通过改变各种钠，钙和钾来激发神经元 频道。这种兴奋性调节在 胆碱能调节清醒，认知和记忆。目标 拟议的研究是了解毒蕈碱行动变化 根据调制 特定的离子通道。斑块夹技术将用于研究 控制钠，钾，钙通道的交感神经， 毒蕈碱刺激通过海马和多巴胺神经元。主要 实验制剂将是急性隔离的神经元，这允许 电压钳具有足够的速度，以表征 在动作电位期间，大型的快速电流流动。这将扩展 先前使用脑切片的工作，其中只有相对较小且缓慢 电流可以在电压夹下进行研究。我们将直接检查 通过首次记录动作在动作电位期间流动的电流 潜在的波形形式，在同一单元格中，使用这些波形形式为 电压夹具实验中的命令电压。通过使用药理 分离单个电流沙子的工具，表现两种电流钳 在存在乙酰胆碱的情况下，电压钳实验应 有可能确定特定通道调制的作用 对兴奋性总体变化的贡献类型。毒蕈碱 控制离子通道和神经元兴奋性是一个基本过程 大脑的正常操作，证据表明 衰老的大脑。海马神经元毒蕈碱调节的变化可能 集中参与阿尔茨海默氏病的症状，更好 对所涉及的渠道的理解可能会导致新颖的治疗性 干预措施，例如使用离子通道阻滞剂来模仿效果 乙酰胆碱。