Voltage-Gated Calcium Channels in Nociceptors and Mechanoreceptors

伤害感受器和机械感受器中的电压门控钙通道

• 批准号: 10656868
• 负责人: Diane Lipscombe
• 金额: $ 8.33万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656868
• 关键词: Address; Afferent Neurons; Architecture; Behavior; Behavioral; Binding; Binding Proteins; Brain; CCCTC-binding factor; Calcium; Calcium Channel; Calcium Signaling; Capsaicin; Cell Line; Cells; Chromatin; Collaborations; DNMT3a; Detection; Disease; Enzymes; Epigenetic Process; Event; Exons; Functional disorder; Gatekeeping; Gene Chips; Genes; Genetic; Glutamates; Hypersensitivity; Inflammation; Injury; Investigation; Ion Channel; Link; Location; Maintenance; Mammalian Cell; Measures; Mechanical Stimulation; Mechanics; Mechanoreceptors; Messenger RNA; Methodology; Methods; Methylation; Modeling; Molecular; Morphine; Mouse Strains; Nerve; Nerve Endings; Nervous system structure; Neuraxis; Neurons; Neurosciences; Nociception; Nociceptors; Pain; Pattern; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persons; Pharmacology; Process; Property; Protein Isoforms; Proteins; RNA; RNA Splicing; Research; Role; Sensory; Signal Transduction; Site; Skin; Specificity; Spinal cord posterior horn; Stimulus; Substance P; Synapses; Testing; Touch sensation; United States; Zinc Fingers; bisulfite sequencing; chronic pain; chronic painful condition; defined contribution; experience; experimental study; genetic approach; healing; improved; in vivo; in vivo calcium imaging; in vivo imaging; mRNA Precursor; mechanical signal; mechanical stimulus; nerve injury; novel; optogenetics; pain model; pain perception; presynaptic; response; sensory system; tissue injury; transmission process; treatment strategy; voltage

Voltage-gated calcium ion channels are critically important proteins that regulate release of glutamate and substance P from nociceptors in the superficial dorsal horn of the spinal cord. As such, they serve as the gatekeepers, at the junction of the periphery and central nervous system, conveying information about touch, heat, mechanical stimulation and more to the brain. High heat or strong mechanical stimuli are noxious and perceived in the brain as painful. Neurons that detect potentially harmful signals, such as high heat, are essential for protecting the body against damage. In response to continued stimulation, such as occurs in tissue injury, these neurons can sensitize as part of a protective response, but their sensitivity usually returns to normal after healing. In certain chronic pain conditions, such as after peripheral nerve injury, the sensitivity of nociceptors fails to return to pre injury levels and normal heat and touch continue to be perceived as painful. This persistence of sensitization combined with ongoing spontaneous activity of pain circuits can result in unrelenting, chronic pain. Understanding the molecular and cellular changes that occur during the transition from normal to chronic pain states are the key to improving current – inadequate – therapies. This proposal builds on our recent discoveries and our unique expertise to determine the role of voltage-gated calcium ion channels in sensory neurons that contribute to chronic pain. We study Cacna1a and Cacna1b genes that encode the core subunits of two calcium ion channels, CaV2.1 and CaV2.2, that control transmitter release at the majority of synapses in the mammalian nervous system. We tackle two critically important questions in our overall objective to elucidate the molecular mechanisms that orchestrate Cacna1a and Cacna1b processing and their actions in different subtypes of sensory neurons that transmit information about thermal and mechanical stimuli: Aim 1. What cellular factors control the expression of the major forms of CaV2 channels in thermal and mechanical signaling? What molecular changes disrupt the normal pattern of expression of these calcium ion channels in chronic pain? Aim 2. How do different calcium ion channels function in thermal and mechanical signaling at peripheral nerve endings in skin? And do the abnormal expression patterns of different forms of ion channels contribute to the induction and maintenance of abnormal signaling? Our research addresses major gaps in our understanding, and the results will contribute to new strategies and reveal new targets for pharmacological or genetic approaches, to mitigate certain forms of chronic pain experienced by millions of people in the United States.

电压门控钙离子通道是非常重要的蛋白质，可调节谷氨酸的释放和 脊髓浅表背角中的伤害感受器的物质。因此，它们是 守门人，在外围和中枢神经系统的交界处，传达了有关触摸的信息， 热量，机械刺激以及更多对大脑的刺激。高热量或强大的机械刺激有害，并且 在大脑中被认为是痛苦的。检测到潜在有害信号的神经元，例如高热量，是 保护身体免受损伤至关重要。响应持续刺激，例如 组织损伤，这些神经元可以作为受保护反应的一部分感觉，但它们的灵敏度通常会返回 愈合后正常。在某些慢性疼痛状况下，例如在周围神经损伤后，灵敏度 伤害感受器无法恢复受伤的水平，正常的热量和触摸仍然被认为是痛苦的。 灵敏度的这种持续性与疼痛回路的持续赞助活动相结合可能导致 持续的，慢性疼痛。了解过渡期间发生的分子和细胞变化 从正常到慢性疼痛状态是改善电流（不充分）疗法的关键。这个建议 建立在我们最近的发现和我们独特的专业知识的基础上，以确定电压门控钙离子的作用 感觉神经元中导致慢性疼痛的通道。我们研究Cacna1a和Cacna1b基因 编码两个钙离子通道Cav2.1和cav2.2的核心亚基，该控制器控制发射机在 哺乳动物神经系统中的大多数突触。我们解决了两个至关重要的问题 阐明协调CACNA1A和CACNA1B处理的分子机制的总体目标 以及它们在感官神经元不同亚型中的作用，这些神经元传输有关热和热的信息 机械刺激：目标1。哪些细胞因子控制着Cav2通道的主要形式的表达 热和机械信号？什么分子变化破坏了这些的正常表达方式 慢性疼痛中的钙离子通道？目标2。不同的钙离子通道在热和 皮肤周围神经结尾处的机械信号传导？并执行不同的异常表达模式 离子通道的形式有助于异常信号传导的诱导和维持？我们的研究 解决我们理解中的主要差距，结果将有助于新策略并揭示 药物或遗传方法的靶标，以减轻某些形式的慢性疼痛。 在美国成千上万的人。