Calcium regulation of spontaneous release of GABA

GABA 自发释放的钙调节

基本信息

  • 批准号:
    8890254
  • 负责人:
  • 金额:
    $ 4.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Synaptic transmission occurs through the release of neurotransmitter from vesicles and the subsequent activation of a postsynaptic voltage change. It underlies every aspect of brain function and is relevant to neurological diseases. The key step in synaptic transmission, vesicle fusion, is dependent on Ca2+ entry through presynaptic voltage-gated Ca2+ channels (VGCCs) that are activated by an action potential. However, despite many years of study, the role of VGCCs in regulating spontaneous vesicle fusion in the absence of an action potential is not clear. VGCCs are tightly coupled to the release machinery for spontaneous release of the inhibitory neurotransmitter GABA in cortical neurons, and multiple VGCCs cooperate in triggering spontaneous release at these synapses. Additionally, activation of the Ca2+-sensing receptor (CaSR) by Ca2+ facilitates spontaneous GABA release. The goal of this proposal is to improve understanding of the role of Ca2+ in regulating neurotransmitter release, specifically how it is different at different types of synapse and for different forms of release. The overall hypothesis is that spontaneous and action potential-dependent release of GABA are regulated by Ca2+ via distinct mechanisms. This hypothesis will be tested in neocortical neuronal cultures using whole-cell voltage-clamp recordings of inhibitory postsynaptic currents to detect release of GABA and Ca2+ imaging to monitor changes in intraterminal Ca2+. Aim 1 is to determine how VGCCs regulate GABA release. The first experiment in this proposal will use Ca2+ chelators, EGTA and BAPTA, to test if the diffusion distance for calcium from VGCCs to the vesicle release machinery for activity-evoked release of GABA is different from that observed for spontaneous GABA release. The next experiment in this aim will use Ca2+ imaging to determine if changes in the extracellular Ca2+ concentration produce changes in the intraterminal Ca2+ concentration in GABAergic neurons. The final experiment in this aim will investigate the mechanism underlying VGCC cooperativity for spontaneous GABA release. This could occur through two possible mechanisms: (i) physiological coupling through linkage of multiple channels or (ii) stochastic synchronized gating. Both of these possibilities will be investigated by measuring VGCC cooperativity for spontaneous GABA release in cultured neurons from VGCC knock-out mice that are transfected with mutant VGCCs, lacking their C-terminal tails, and computer modeling and Monte Carlo simulation. Aim 2 will determine how the CaSR regulates spontaneous GABA release. These experiments will use pharmacological tools and intracellular Ca2+-imaging to determine the players in the CaSR-signaling pathway. Together, this proposal will provide an understanding of the role of Ca2+ in regulating synaptic transmission. Understanding the mechanism by which Ca2+ influences release of neurotransmitter will contribute to an improved understanding of synaptic function in general and when transmission is disrupted in disease states.
描述(由申请人提供):突触传递通过从囊泡释放神经递质和随后激活突触后电压变化而发生。它是大脑功能各个方面的基础,与神经系统疾病有关。突触传递中的关键步骤,囊泡融合,依赖于通过突触前电压门控Ca 2+通道(VGCC)的Ca 2+进入,所述VGCC由动作电位激活。然而,尽管多年的研究,在没有动作电位的情况下,VGCC在调节自发囊泡融合中的作用尚不清楚。VGCC与皮质神经元中抑制性神经递质GABA自发释放的释放机制紧密耦合,并且多个VGCC在触发这些突触处的自发释放中合作。此外,Ca 2+对Ca 2+敏感受体(CaSR)的激活促进自发GABA释放。该提案的目标是提高对Ca 2+在调节神经递质释放中的作用的理解,特别是它在不同类型的突触和不同形式的释放中是如何不同的。总体假设是GABA的自发和动作电位依赖性释放由Ca 2+通过不同的机制调节。将在新皮层神经元培养物中使用抑制性突触后电流的全细胞电压钳记录来检测GABA的释放和Ca 2+成像来监测末端内Ca 2+的变化,从而检验这一假设。目的1是确定VGCC如何调节GABA的释放。在这个建议的第一个实验将使用钙离子螯合剂,EGTA和BAPTA,以测试如果钙从VGCC的囊泡释放机制的活动诱发释放GABA的扩散距离是不同于自发释放GABA观察。该目标的下一个实验将使用Ca 2+成像来确定细胞外Ca 2+浓度的变化是否会导致GABA能神经元中末端内Ca 2+浓度的变化。最后一个实验将探讨VGCC协同自发释放GABA的机制。这可以通过两种可能的机制发生:(i)通过多个通道的连接的生理耦合或(ii)随机同步门控。这两种可能性将通过测量VGCC协同自发GABA释放培养的神经元从VGCC基因敲除小鼠,转染突变VGCC,缺乏其C-末端尾巴,和计算机建模和蒙特卡洛模拟。目的2将确定CaSR如何调节自发GABA释放。这些实验将使用药理学工具和细胞内Ca 2+成像来确定CaSR信号通路中的参与者。总之,这一建议将提供一个理解的作用,钙离子在调节突触传递。了解Ca 2+影响神经递质释放的机制将有助于更好地理解突触功能,以及疾病状态下传递中断的情况。

项目成果

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Courtney L Williams其他文献

Courtney L Williams的其他文献

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{{ truncateString('Courtney L Williams', 18)}}的其他基金

Calcium regulation of spontaneous release of GABA
GABA 自发释放的钙调节
  • 批准号:
    8649426
  • 财政年份:
    2013
  • 资助金额:
    $ 4.31万
  • 项目类别:
Calcium regulation of spontaneous release of GABA
GABA 自发释放的钙调节
  • 批准号:
    8775607
  • 财政年份:
    2013
  • 资助金额:
    $ 4.31万
  • 项目类别:

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