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: 7624841
• 负责人: LISA H KREINER
• 金额: $ 0.69万
• 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 2008-06-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624841
• 关键词: Affect; Agonist; Ataxia; Binding; Binding Sites; Biological; Brain; Buffers; CAT development factor; Calmodulin; Cell Death; Cell membrane; Cell physiology; Cells; Chromosome Pairing; Complex; Defect; Disease; Dose; Electrophysiology (science); Epilepsy; Familial Hemiplegic Migraine; Feedback; Fellowship; Genetic Transcription; Guanine Nucleotide Dissociation Inhibitors; Imaging Techniques; Individual; Ions; LIF gene; Mediating; Membrane; Molecular Biology; Mus; Names; Nervous system structure; Neurons; P-Q type voltage-dependent calcium channel; Parvalbumins; Pathology; Pathway interactions; Phosphorylation; Physiological; Process; Property; Proteins; Range; Regulation; Research; Role; Signal Pathway; Signal Transduction; Solutions; Spinocerebellar Ataxias; Stimulus; Synapses; System; Testing; Time; Whole-Cell Recordings; cell type; cyclophosphamide/doxorubicin/fluorouracil protocol; insight; mutant; neurotransmitter release; novel; patch clamp; research study; voltage

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 determinantsof 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 Ca~+ 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 mieraine. eoileosv. and ataxia.

电压门控的Ca2+通道将膜去极化到Ca2+流入细胞中，这引发了宽阔的 生物学上重要的过程，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，它们的活性受多种形式的影响 规定。特别是，Cav2.1（p/q-type）Ca2+通道经过Ca2+离子的双反馈调节 在某些突触时有助于短期可塑性。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）。促进和灭活都是Ca2+依赖性的，因此可以 受神经元中细胞内Ca2+水平的因素的影响。本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，细胞内Ca2+ 商店可能是Cav2.1调节Ca2+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通道的程度 Ca2+。全细胞斑块夹电生理学，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+商店如何影响CAV2.1的活动依赖反馈 Ca〜+都在转染的细胞和分离的神经元中。这项研究的发现可能揭示了新的机制 神经元中Cav2.1通道的异质特性的基础，并为替代方案提供新的见解 治疗与CA2+通道缺陷相关的疾病的策略，例如Mieraine。 eoileosv。和共济失调。