Factors regulating Cav 2.1 modulation by Ca2+ in neurons

电压门控性Ca 2+通道将膜去极化与Ca 2+流入细胞偶联，这引发了广泛的细胞内钙离子通道。 多种生物学重要过程，包括磷酸化、基因转录和神经递质释放。 由于这些Ca 2+通道对于细胞信号传导的重要性，它们的活性受到多种形式的影响。 调控特别地，Cav2.1（P/Q型）Ca 2+通道经历由Ca 2+离子的双重反馈调节， 有助于某些突触的短期可塑性。在重复刺激期间，Cav2.1 Ca 2+电流最初增加， （方便），逐渐减少（减少）。易化和失活都是Ca 2+依赖性的，因此可以 受控制神经元细胞内Ca 2+水平的因素影响。本提案提出的初步结果 表明在某些神经元中以高浓度存在的Ca 2+缓冲蛋白和细胞内Ca 2+缓冲蛋白， Ca ~（2+）对Ca ~（2+）调节Ca ~（2.1）的作用可能是Ca ~（2+）调节Ca ~（2.1）的重要因素。研究计划中概述的实验将 检验这些因素严重影响神经元Cav2.1通道受以下因素调节的程度的假设： Ca2+。全细胞膜片钳电生理学、分子生物学和Ca 2+成像技术将用于 表征Ca 2 * 缓冲蛋白和细胞内Ca 2+储存如何影响Cav2.1的活性依赖性反馈， Ca~+在转染细胞和分离的神经元中均存在。这项研究的结果可能揭示新的机制， 揭示了神经元中Cav2.1通道的异质性，并为替代疗法提供了新的见解 治疗与Ca 2+通道缺陷相关的疾病的策略，如mieraine。埃奥伊勒奥斯夫。和共济失调

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.