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Store-operated calcium channels in neuropathic pain

神经性疼痛中钙池操纵的钙通道

基本信息

批准号：
8465926
负责人：
Huijuan Hu
金额：
$ 18.64万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465926
关键词：
Address Animals Calcium Calcium Channel Calcium Signaling Cations Cell physiology Cells Chemosensitization Clinical Coupled Data Dependency Development Endoplasmic Reticulum Family Gene Silencing Genes Goals Hypersensitivity Image Individual Ion Channel Ions Ischemia Laboratories Ligation Maintenance Mediating Methods Modeling Molecular Molecular Target Nature Nervous system structure Neuronal Plasticity Neurons Nociception Operative Surgical Procedures Outcomes Research Pain Pathway interactions Persistent pain Physicians Play Posterior Horn Cells Potassium Channel Property Proteins Protocols documentation RNA Interference Role Signal Pathway Signal Transduction Small Interfering RNA Societies Spinal Spinal Cord Spinal nerve structure Synaptic Transmission Synaptic plasticity Testing Time base behavior test chronic pain human STIM1 protein in vivo knock-down ligand gated channel nerve injury neurotransmitter release new therapeutic target novel painful neuropathy patch clamp receptor sensor transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain represents a clinical challenge for the practicing physician and is a great burden to society. Although the mechanisms underlying neuropathic pain remain to be established, calcium-permeable ion channels and receptors have been implicated in pain as well as in the neuroplasticity associated with chronic pain states. Store-operated calcium (SOC) channels are highly Ca2+-selective cation channels that are activated by the release and depletion of calcium from the endoplasmic reticulum. Activation of SOC channels leads to sustained high cytosolic Ca2+ levels that are required for many calcium-dependent cellular processes. SOC channels are composed of newly discovered Orai subunits (Orai1/2/3, pore- forming subunits), and stromal interaction molecules (STIM) 1 and STIM2 (the ER Ca2+ sensors, serve as their activators) in non-excitable cells. In the nervous system, SOC channels are known to influence neurotransmitter release and synaptic plasticity. STIM2 is essential for ischemia-induced cytosolic Ca2+ accumulation in neurons, but the basic properties of SOC channels and molecular components underlying SOC channels in neurons are unexplored. Recently, we found that SOC channels are functionally expressed in spinal dorsal horn neurons and demonstrated that activation of SOC channels is involved in synaptic transmission. These observations raise questions as to the function of SOC channels and to the nature of the signaling pathways that are coupled to the activation of these channels in pain signal transmission. We also found that the expression of the SOC channels is upregulated at different time points after spare nerve injury (SNI). Based on these findings, we hypothesize that the SOC channels may play a role in neuronpathic pain. To test our hypothesis, we will combine the methods of patch-clamp recording, calcium imaging recording, Taqman real-time-PCR and behavioral testing. Overall, our long-term goal is to identify key molecular targets involved in chronic pain. The goals of this proposal are to determine basic properties of SOC channels, to identify molecules encoding SOC channels in dorsal horn neurons, and to determine the role of SOC channel family in neuropathic pain. The expected outcome of this research is the identification of new calcium signaling in pain pathway and a new mechanism underlying the development and maintenance of neuropathic pain.

描述（由申请人提供）：神经性疼痛对执业医师来说是一种临床挑战，也是社会的巨大负担。尽管神经性疼痛的机制仍有待确定，但钙渗透性离子通道和受体与疼痛以及与慢性疼痛状态相关的神经可塑性有关。钙库操纵 (SOC) 通道是高度 Ca2+ 选择性的阳离子通道，通过内质网钙的释放和消耗而激活。 SOC 通道的激活导致胞质 Ca2+ 水平持续升高，这是许多钙依赖性细胞过程所必需的。 SOC通道由非兴奋细胞中新发现的Orai亚基（Orai1/2/3，成孔亚基）和基质相互作用分子（STIM）1和STIM2（ER Ca2+传感器，作为其激活剂）组成。在神经系统中，SOC 通道会影响神经递质释放和突触可塑性。 STIM2 对于缺血诱导的神经元细胞质 Ca2+ 积累至关重要，但神经元 SOC 通道的基本特性和 SOC 通道的分子成分尚未被探索。最近，我们发现SOC通道在脊髓背角神经元中功能性表达，并证明SOC通道的激活参与突触传递。这些观察结果对 SOC 通道的功能以及与疼痛信号传输中这些通道的激活相关的信号通路的性质提出了疑问。我们还发现，备用神经损伤（SNI）后不同时间点SOC通道的表达上调。基于这些发现，我们假设 SOC 通道可能在神经病理性疼痛中发挥作用。为了检验我们的假设，我们将结合膜片钳记录、钙成像记录、Taqman 实时 PCR 和行为测试的方法。总体而言，我们的长期目标是确定与慢性疼痛有关的关键分子靶点。该提案的目标是确定 SOC 通道的基本特性，识别背角神经元中编码 SOC 通道的分子，并确定 SOC 通道家族在神经性疼痛中的作用。这项研究的预期结果是鉴定疼痛通路中新的钙信号传导以及神经性疼痛发生和维持的新机制。