Store-operated calcium channels in neuropathic pain

神经性疼痛中钙池操纵的钙通道

• 批准号: 8386191
• 负责人: Huijuan Hu
• 金额: $ 23.18万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 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/8386191
• 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

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. PUBLIC HEALTH RELEVANCE: Store-operated calcium (SOC) channels are activated by the release and depletion of calcium, are expressed in spinal dorsal horn neurons and, based on preliminary studies in our laboratory, appear to play a role in pain. The primary objective of this proposal is to identify the molecular components of SOC channels and to explore the definitive role of the SOC channel family in neuropathic pain with a view towards identifying new therapeutic targets.

描述（由申请人提供）：神经性疼痛代表了实践医师的临床挑战，是社会的巨大负担。尽管仍有神经性疼痛的机制尚待确定，但钙可渗透的离子通道和受体与疼痛以及与慢性疼痛状态相关的神经塑性有关。商店经营的钙（SOC）通道是高度Ca2+选择性阳离子通道，通过从内质网释放和耗尽而激活的阳离子通道。 SOC通道的激活导致许多依赖钙依赖性细胞过程所需的高胞质Ca2+水平。 SOC通道由新发现的ORAI亚基（Orai1/2/3，孔形成亚基）和基质相互作用分子（stim）1和stim2（ER Ca2+传感器，作为其激活剂）在不可脱离的细胞中。在神经系统中，已知SOC通道会影响神经递质释放和突触可塑性。 STIM2对于神经元中缺血诱导的胞质CA2+积累至关重要，但是神经元中SOC通道下的SOC通道和分子成分的基本特性没有探索。最近，我们发现SOC通道在脊柱背角神经元中功能表达，并证明SOC通道的激活与突触传播有关。这些观察结果提出了有关SOC通道功能以及信号通路的性质的问题，这些信号通路与这些通道在疼痛信号传递中的激活相结合。我们还发现，备用神经损伤（SNI）后，SOC通道的表达在不同的时间点上调。根据这些发现，我们假设SOC渠道可能在神经性疼痛中起作用。为了检验我们的假设，我们将结合贴片钳记录，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标。该提案的目标是确定SOC通道的基本特性，确定编码背角神经元中SOC通道的分子，并确定SOC渠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途径中新的钙信号传导以及神经性疼痛发育和维持的新机制。 公共卫生相关性：商店经营的钙（SOC）通道通过钙的释放和耗竭激活，在脊柱背角神经元中表达，并且基于我们实验室的初步研究，似乎在疼痛中起作用。这是这个的主要目标 建议是确定SOC通道的分子成分，并探索SOC通道家族在神经性疼痛中的明确作用，以确定新的治疗靶标。