A novel cation channel in excitatory neuronal injury

兴奋性神经元损伤中的新型阳离子通道

基本信息

批准号：
7379919
负责人：
ZHIGANG XIONG
金额：
$ 30.59万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7379919
关键词：
AMPA Receptors Affect Affinity Antibiotics Bathing Brain Brain Ischemia Calcium Carbenoxolone Cations Cells Characteristics Chemosensitization Condition Data Dependence Development Disease Dose Down-Regulation Dyes Fractionation Free Radical Scavengers Gadolinium Glucose Glutamate Receptor GsMTx-4 toxin Heptanol High Pressure Liquid Chromatography Hippocampus (Brain)Homeostasis Hypoxia Image Imaging Techniques In Vitro Injury Ion Channel Ions Ischemia Ischemic Brain Injury Ischemic Neuronal Injury Lipids Mediating Membrane Membrane Potentials Modeling Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate Neomycin Neuraxis Neuronal Injury Neurons Numbers Oxygen Pathology Peptides Permeability Personal Satisfaction Phospholipase C Physiological Processes Play Principal Investigator Property Protocols documentation Regulation Reporting Research Personnel Role Screening procedure Signal Transduction Slice Spider Venoms Spiders Standards of Weights and Measures Stretching Synaptic Transmission System Tarantula Venoms Techniques Testing Thapsigargin Time Tissues Toxic effect Toxin Turtles Venoms channel blockers deprivation excitotoxicity expression cloning extracellular gap junction channel in vitro Model in vivo ligand gated channel mature animal nervous system disorder neuronal excitability novel patch clamp prevent programs receptor research study response voltage

项目摘要

DESCRIPTION (provided by applicant): Calcium is one of the most important ions in the central nervous system, essential for the regulation of neuronal excitability, synaptic transmission, neuronal development and differentiation. Alterations of Ca2+ homeostasis have been shown to be involved in the pathology of various neurological diseases/disorders. Accumulation of intracellular Ca2+ ([Ca2+]i), for example, has been recognized as a central pathological feature in brain ischemia. Along with an increase in [Ca2+]i, ischemia also causes a dramatic decrease in the concentration of extracellular Ca2+ ([Ca2+]e). Although it is well-known that the increase of [Ca2+]j is critical for excitatory neuronal injury, it is not clear whether the alteration of [Ca2+]e plays any role in the pathology of brain ischemia. We have previously demonstrated that lowering [Ca2+]e to the level commonly seen in brain ischemia strongly depolarized and excited cultured hippocampal neurons through activation of a non-selective cation channel. This channel has electrophysiological properties and pharmacological profiles different from known channels, suggesting activation of a novel Ca2+-sensitive ion channel. Our preliminary study also demonstrated that activation of this channel caused an increase in [Ca2+]i and potentiated NMDA-receptor mediated membrane responses as well as neuronal injury. We therefore hypothesize that decreases of [Ca2+]e to the level seen in brain ischemia activates a distinct Ca2+-sensing non-selective cation (csNSC) channel. Activation of these channels induces membrane depolarization and neuronal excitation, which contributes to excitotoxicity either directly, or indirectly through potentiation of NMDA receptor mediated responses. Our objective is to provide additional evidence that csNSC is indeed a distinct new channel and to investigate its pathological role in hypoxic/ischemic neuronal injury. In addition to cultured neurons, we will characterize detailed electrophysiological properties of the csNSC channel in acutely dissociated mature neurons and the neurons in brain slices, develop a pharmacological profile and search for a specific channel blocker. We will define the Ca2+-permeability of the csNSC channel, and determine whether ischemic treatment enhances the Ca2+-permeability. Since NMDA channels play a critical role in excitatory neuronal injury, we will characterize detailed interaction of csNSC channels with NMDA receptor-mediated membrane responses and neuronal injury. Using in vitro ischemic models, we will determine whether preventing the activation of csNSC channels protects neurons from ischemic injury. Specific Aims are: 1. Provide further evidence that lowering [Ca2+]e to the level seen in brain ischemia activates a distinct nonselective cation channel in the central nervous system. 2. Demonstrate that csNSC channels are Ca2+-permeable. 3. Demonstrate potentiation of NMDA channel function by csNSC activation. 4; Determine the potential role of csNSC channels in ischemic neuronal injury.

描述（由申请人提供）：钙是中枢神经系统中最重要的离子之一，对于调节神经元兴奋性，突触传播，神经元发育和分化至关重要。 CA2+稳态的改变已被证明与各种神经系统疾病/疾病的病理有关。例如，细胞内Ca2+（[Ca2+] i）的积累已被认为是脑缺血中的中心病理特征。随着[Ca2+] I的增加，缺血还会导致细胞外Ca2+（[Ca2+] E）的浓度急剧下降。尽管众所周知，[Ca2+] J的增加对于兴奋性神经元损伤至关重要，但尚不清楚[Ca2+] e的改变是否在脑缺血病理学中起任何作用。我们先前已经证明，通过激活非选择性阳离子通道，将[Ca2+] E降低到脑缺血中常见的水平强烈去极化和激发的海马神经元。该通道具有与已知通道不同的电生理特性和药理学特征，表明新型Ca2+敏感离子通道的激活。我们的初步研究还表明，该通道的激活导致[Ca2+] I的增加，并增强NMDA受体介导的膜反应以及神经元损伤。因此，我们假设将[Ca2+] E降低到脑缺血中所见水平会激活独特的Ca2+sensed非选择性阳离子（CSNSC）通道。这些通道的激活诱导膜去极化和神经元激发，这会导致兴奋性直接或通过增强NMDA受体介导的反应的增强。我们的目标是提供其他证据，表明CSNSC确实是一个独特的新通道，并研究其在缺氧/缺血性神经元损伤中的病理作用。除培养的神经元外，我们还将表征CSNSC通道在急性解散的成熟神经元和脑切片中神经元中的详细电生理特性，发展药理特征并寻找特定的通道阻滞剂。我们将定义CSNSC通道的Ca2+渗透性，并确定缺血治疗是否增强了Ca2+ - 渗透率。由于NMDA通道在兴奋性神经元损伤中起着至关重要的作用，因此我们将表征CSNSC通道与NMDA受体介导的膜反应和神经元损伤的详细相互作用。使用体外缺血模型，我们将确定防止CSNSC通道的激活能够保护神经元免受缺血性损伤。具体目的是：1。提供进一步的证据，表明将[Ca2+] E降低到脑缺血中看到的水平会激活中枢神经系统中独特的非选择性阳离子通道。 2。证明CSNSC通道是Ca2+可渗透的。 3。通过CSNSC激活证明NMDA通道功能的增强。 4;确定CSNSC通道在缺血性神经元损伤中的潜在作用。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Carboxypeptidase E knockout mice exhibit abnormal dendritic arborization and spine morphology in central nervous system neurons.

羧肽酶 E 敲除小鼠在中枢神经系统神经元中表现出异常的树突状树枝化和脊柱形态。

DOI：
10.1002/jnr.22174
发表时间：
2010-01
期刊：
JOURNAL OF NEUROSCIENCE RESEARCH
影响因子：
4.2
作者：
Woronowicz, Alicja;Cawley, Niamh X.;Chang, Su-Youne;Koshimizu, Hisatsugu;Phillips, Andre W.;Xiong, Zhi-Gang;Loh, Y. Peng
通讯作者：
Loh, Y. Peng