Voltage-Gated Calcium Channels in Nociceptors and Mechanoreceptors

电压门控钙离子通道是调节谷氨酸和 来自脊髓背角浅层伤害性感受器的P物质。因此，它们充当 守门人，在外周和中枢神经系统的交界处，传递关于触摸的信息， 热量、机械刺激和更多对大脑的影响。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。检测潜在有害信号的神经元，如高热，是 对保护身体免受伤害是必不可少的。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敏化，但它们的敏感度通常会恢复 痊愈后恢复正常。在某些慢性疼痛情况下，如周围神经损伤后，敏感度 伤害性感受器的大部分未能恢复到受伤前的水平，正常的高温和触摸仍然被认为是疼痛的。 这种敏感化的持续性与痛觉回路持续的自发活动相结合，可能会导致 无休止的慢性疼痛。了解在过渡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方法的关键。这项建议 以我们最新的发现和我们独特的专业知识为基础，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。我们研究了Cacna 1a和Cacna 1b基因 编码控制递质释放的两个钙离子通道CaV2.1和Cav2.2的核心亚单位 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 总体目标是阐明协调Cacna 1a和Cacna 1b加工的分子机制 以及它们在不同亚型感觉神经元中的作用，这些感觉神经元传递关于温度和 机械刺激：目的1.哪些细胞因素控制CaV2通道的主要形式的表达 热信号和机械信号？是什么分子变化扰乱了这些基因的正常表达模式 钙离子通道与慢性疼痛？目的2.不同的钙离子通道是如何在热和热应激中发挥作用的 皮肤周围神经末梢的机械信号？以及不同基因的异常表达模式 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 解决了我们在理解上的主要差距，结果将有助于制定新的战略并揭示新的 药物或遗传方法的目标，以减轻某些形式的慢性疼痛 数以百万计的美国人。

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.