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释放的重要蛋白质， 来自脊髓背角浅层的伤害感受器的P物质。因此，它们作为 看门人，在外围和中枢神经系统的交界处，传达有关触摸的信息， 热，机械刺激和更多的大脑。高温或强烈的机械刺激是有害的， 在大脑中被认为是痛苦的。神经元检测潜在的有害信号，如高温， 对保护身体免受伤害至关重要。对持续刺激的反应，如发生在 组织损伤时，这些神经元可以作为保护性反应的一部分而致敏，但它们的敏感性通常会恢复。 恢复正常后。在某些慢性疼痛条件下，例如周围神经损伤后， 的伤害感受器不能恢复到受伤前的水平，正常的热和触摸继续被认为是痛苦的。 这种持续的致敏作用与疼痛回路的持续自发活动相结合，可导致 持续的慢性疼痛了解在转变过程中发生的分子和细胞变化 从正常疼痛状态到慢性疼痛状态是改善目前不足的治疗的关键。这项建议 建立在我们最近的发现和我们独特的专业知识，以确定电压门控钙离子的作用， 导致慢性疼痛的感觉神经元通道。我们研究了Cacna1a和Cacna1b基因， 编码两个钙离子通道CaV2.1和CaV2.2的核心亚基，CaV2.1和CaV2.2控制递质释放， 哺乳动物神经系统中的大多数突触。我们在我们的课程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加工的分子机制 以及它们在不同亚型的感觉神经元中的作用，这些感觉神经元传递关于热的信息， 机械刺激：目标1。什么样的细胞因子控制CaV 2通道的主要形式在细胞中的表达？ 热和机械信号哪些分子变化会破坏这些蛋白的正常表达模式 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传导和 皮肤周围神经末梢的机械信号不同的基因的异常表达模式 离子通道的形式有助于诱导和维持异常信号？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 药理学或遗传学方法的靶点，以减轻某些形式的慢性疼痛， 在美国有数百万人。