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调节谷氨酸和 来自脊髓浅表背角伤害感受器的 P 物质。因此，它们充当 守门人，位于外周和中枢神经系统的交界处，传递有关触摸的信息， 热量、机械刺激等对大脑的刺激。高热或强烈的机械刺激是有毒的，并且 在大脑中被感知为疼痛。检测潜在有害信号（例如高热）的神经元是 对于保护身体免受伤害至关重要。响应持续的刺激，例如发生在 当组织损伤时，这些神经元可以作为保护反应的一部分变得敏感，但它们的敏感性通常会恢复 痊愈后恢复正常。在某些慢性疼痛情况下，例如周围神经损伤后，敏感性 伤害感受器未能恢复到受伤前的水平，正常的热度和触摸仍然被认为是疼痛的。 这种持续的敏化与疼痛回路持续的自发活动相结合可导致 持续不断的慢性疼痛。了解转变过程中发生的分子和细胞变化 从正常疼痛状态转变为慢性疼痛状态是改善当前不足的疗法的关键。这个提议 基于我们最近的发现和独特的专业知识来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，控制递质释放 哺乳动物神经系统中的大部分突触。我们在我们的研究中解决了两个至关重要的问题 总体目标是阐明协调 Cacna1a 和 Cacna1b 处理的分子机制 以及它们在不同亚型的感觉神经元中的作用，这些神经元传递有关热和信息的信息 机械刺激：目标 1. 哪些细胞因子控制 CaV2 通道主要形式的表达 热信号和机械信号？哪些分子变化破坏了这些基因的正常表达模式 慢性疼痛中的钙离子通道？目标 2. 不同的钙离子通道如何在热和 皮肤周围神经末梢的机械信号？并做不同的异常表达模式 离子通道的形式有助于异常信号的诱导和维持？我们的研究 解决了我们理解中的主要差距，其结果将有助于制定新的战略并揭示新的 药理学或遗传方法的目标，以减轻某些形式的慢性疼痛 美国有数百万人。