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谷氨酸释放的重要蛋白