Factors regulating Cav 2.1 modulation by Ca2+ in neurons

神经元中 Ca2 调节 Cav 2.1 的调节因素

• 批准号: 6936720
• 负责人: LISA H KREINER
• 金额: $ 2.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-09 至 2008-02-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936720
• 关键词: calcium binding protein; calcium channel; calcium flux; calcium ion; cerebellar Purkinje cell; genetically modified animals; granule cell; laboratory mouse; neural facilitation; neural inhibition; predoctoral investigator; tissue /cell culture; transfection; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Voltage-gated Ca2+ channels couple membrane depolarization to the influx of Ca2+ into the cell, which initiates a wide variety of biologically important processes including phosphorylation, gene transcription and neurotransmitter release. Because of the importance of these Ca2+ channels for cellular signaling, their activity is subject to numerous forms of regulation. In particular, Cav2.1 (P/Q-type) Ca2+ channels undergo a dual feedback regulation by Ca2+ ions which contributes to short-term plasticity at some synapses. During repetitive stimuli, Cav2.1 Ca2+ currents initially increase (facilitate) and gradually decrease (inactivate). Both facilitation and inactivation are Ca2+-dependent and therefore can be influenced by factors controlling intracellular Ca2+ levels in neurons. Preliminary results presented in this proposal indicate that Ca2+ buffering proteins, which are present at high concentrations in some neurons, and Ca2+ in intracellular stores may be important determinants of Cav2.1 regulation by Ca2+. The experiments outlined in the research plan will test the hypothesis that these factors critically influence the extent to which neuronal Cav2.1 channels are modulated by Ca2+. Whole-cell patch clamp electrophysiology, molecular biology, and Ca2+ imaging techniques will be used to characterize how Ca2+ buffering proteins and intracellular Ca2+ stores affect activity-dependent feedback of Cav2.1 by Ca2+ both in transfected cells and isolated neurons. The findings from this research may reveal novel mechanisms underlying the heterogeneous properties of Cav2.1 channels in neurons and provide new insights into alternative strategies to treat diseases associated with Ca2+ channel defects, such as migraine, epilepsy and ataxia.

描述（由申请人提供）：电压门控的Ca2+通道将膜去极化到Ca2+流入细胞中，该膜启动了各种各样的生物学重要过程，包括磷酸化，基因转录和神经递质释放。由于这些CA2+通道对细胞信号的重要性，因此它们的活性受到多种形式的调节。特别是，CAV2.1（P/Q-Type）Ca2+通道经过Ca2+离子的双反馈调节，这有助于某些突触时短期可塑性。在重复刺激期间，CAV2.1 Ca2+电流最初增加（促进）并逐渐减少（失活）。促进和失活都是Ca2+依赖性的，因此可能受到控制神经元细胞内Ca2+水平的因素的影响。该提案中提出的初步结果表明，在某些神经元中以高浓度存在的Ca2+缓冲蛋白，而细胞内存储中的Ca2+可能是Ca2+调节Cav2.1调节的重要决定因素。研究计划中概述的实验将检验以下假设：这些因素严重影响神经元Cav2.1通道由Ca2+调节的程度。全细胞贴片夹电生理，分子生物学和Ca2+成像技术将用于表征Ca2+缓冲蛋白和细胞内Ca2+存储如何影响转染的细胞和孤立的神经元中Ca2+的CAV2.1的活性依赖性反馈。这项研究的发现可能揭示了神经元中Cav2.1通道异质性质的基础的新型机制，并为治疗与Ca2+通道缺陷相关的疾病（例如偏头痛，癫痫和双Xa骨）提供了新的见解。