ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING

大脑老化过程中钙通道功能的改变

• 批准号: 6233994
• 负责人: William A Sather
• 金额: $ 13.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6233994
• 关键词: NMDA receptors; acetylcholine; adenosine; aging; biophysics; calcium channel; calcium flux; calmodulin dependent protein kinase; enzyme activity; enzyme inhibitors; gamma aminobutyrate; glutamates; hippocampus; laboratory rat; neuropharmacology; neurotrophic factors; polymerase chain reaction; protein kinase A; protein kinase C; pyramidal cells; voltage /patch clamp; voltage gated channel

cA2+ influx through voltage-gated Ca2+ channels is essential for neurotransmitter release, synaptic plasticity, electrical waveform processing and modification of gene expression in neurons. Yet Ca2+ can also have harmful effects in neurons; modest, sustained elevation of cytoplasmic Ca2+ concentration leads to neuronal degeneration, and ultimately, cell death. Accumulation of such Ca2+ insults has been hypothesized to underlie at least some aspects of brain aging and dementia. As dominant contributors to neuronal Ca2+ signalling, Ca2+ channels represent major potential targets in the search for sources of aging- related neuronal malfunction. Indeed, it has been established over the last several years that the contribution of voltage-gated Ca2+ channels to electrical activity in neurons changes with aging. The principal goal of Project 2 is to delineate mechanisms of aging-induced alteration in the activity of voltage-gated Ca2+ channels in brain neurons. The research plan is directed towards three specific aims: (1) What biophysical properties of Ca2+ channels change with aging? (2) Does aging dependent alteration of Ca2+ channel activity arise from changes intrinsic to the Ca2+ channel? (3) Does aging-dependent alteration of Ca2+ channel activity result from extrinsic influences? The experimental approach takes of advantage of the ability of patch-clamp electrophysiological techniques to detect critical, but potentially subtile, changes in Ca2+ channel behavior in aging. Properties that may change include (i) amplitude of Ca2+ current, (ii) the voltage-dependencies of channel activation, inactivation and deactivation, (iii) efficiency of channel opening, (iv) Ca2+ permeability through the channel or (v) sensitivity to modulation by neurotransmitter-receptors. All of these parameters will be measured and compared as a function of neuron age. The biophysical and pharmacological work will be complemented by efforts to determine whether channel subunit makeup changes with aging. Tissue and single-cell mRNA analyses will be used as a first step towards this goal. The combined electrophysiological and molecular biological approach will provide a synergistic effort to track down the origins of Ca2+ channel dysfunction related to brain aging. Understanding fundamental mechanisms of Ca2+ channel dysfunction in aging will be vital in developing clinical treatments for brain senescence, and perhaps for such dementias as Alzheimer's disease.

通过电压门控Ca 2+通道的Ca 2+内流对于 神经递质释放，突触可塑性，电波形 神经元中基因表达的加工和修饰。 但Ca 2+可以 对神经元也有有害影响; 细胞质Ca 2+浓度导致神经元变性， 最终导致细胞死亡。 这种Ca 2+损伤的积累已经被证明是 被认为是大脑老化和痴呆症的基础。 作为神经元Ca 2+信号传导的主要贡献者，Ca 2+通道 代表了寻找衰老来源的主要潜在目标- 相关的神经元功能障碍。 的确，它是建立在 过去几年，电压门控性Ca 2+通道对 神经元的电活动随着年龄的增长而变化。 的主要目标 项目2是描绘衰老诱导的改变的机制， 脑神经元中电压门控性Ca 2+通道的活性。 研究 该计划旨在实现三个具体目标： (1)Ca 2+通道的生物物理特性随着衰老而变化？ (2)钙通道活性的衰老依赖性改变是否源于 Ca 2+通道的内在变化？ (3)钙通道活性的衰老依赖性改变是否由 外在影响？ 实验方法利用膜片钳技术的特点 电生理技术来检测关键的，但潜在的 微妙的，在老化中的Ca 2+通道行为的变化。 属性可能 改变包括（i）Ca 2+电流的幅度，（ii）电压依赖性 通道激活、失活和失活的效率，（iii） 通道开放，（iv）通过通道的Ca 2+渗透性或（v） 对神经递质受体调节的敏感性。 所有这些 将测量参数并将其作为神经元年龄的函数进行比较。 的 生物物理学和药理学工作将得到以下努力的补充： 确定通道子单元组成是否随老化而改变。 组织和 单细胞mRNA分析将作为实现这一目标的第一步。 结合电生理学和分子生物学的方法将 提供协同努力来追踪Ca 2+通道的起源 与大脑老化有关的功能障碍。 理解基本机制 钙离子通道功能障碍在衰老中的作用将是至关重要的， 治疗大脑衰老，也许还有痴呆症， 老年痴呆症