Regulation of Trigeminal Nociception by TRESK Channels

TRESK 通道对三叉神经伤害感受的调节

• 批准号: 9896858
• 负责人: YUQING CAO
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896858
• 关键词: Address; Adult; Affect; Afferent Neurons; Attenuated; Behavior; Biological Models; Capsaicin; Chronic; Development; Dominant-Negative Mutation; Estrogens; Estrous Cycle; Exhibits; Expression Profiling; Face; Family; Female; Functional disorder; Gene Expression; General Population; Generations; Genetic; Genetic Transcription; Headache; Human; In Vitro; Ion Channel; Knock-out; Knockout Mice; Knowledge; Maintenance; Mediating; Messenger RNA; Migraine; Modeling; Mus; Mutation; Neurons; Nitroglycerin; Nociception; Nociceptors; Outcome; Pain; Pathway interactions; Patients; Physiology; Potassium Channel; Predisposition; Process; Proteins; Regulation; Risk; Spinal Cord; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; System; TRPV1 gene; Testing; Tissues; Transcription Regulatory Protein; Trigeminal Pain; Trigeminal System; Virus; Wild Type Mouse; Withdrawal; Woman; base; behavioral response; follow-up; genetic regulatory protein; insight; interdisciplinary approach; male; mechanical allodynia; mouse model; mutant; neuronal circuitry; neuronal excitability; novel; protein K; transmission process

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in all primary afferent neurons (PANs) in trigeminal ganglion (TG) and dorsal root ganglion (DRG), mediating background K+ currents and controlling the excitability of PANs. However, TRESK mutations cause migraine headache but not body pain in humans, suggesting that TG neurons are more vulnerable to TRESK dysfunctions than DRG neurons. We have found that the migraine-associated TRESK mutation results in the truncation of TRESK protein, which exerts a strong dominant-negative effect on endogenous TRESK current. This has prompted us to use TRESK knockout (KO) mouse as a model system to study the effects of de novo loss of TRESK activity on pain transmission. Despite the ubiquitous loss of TRESK currents in all PANs, only one subpopulation TG neurons in TRESK KO mice becomes hyper-excitable. Unexpectedly, the percentage of capsaicin-responsive neurons is selectively increased in TG but not DRG of KO mice. TRESK KO mice exhibit more robust behavioral responses than wild-type controls in mouse models of trigeminal pain, especially headache. In contrast, wild- type and KO mice respond similarly to noxious stimuli on the hindpaw. These results indicate that TRESK KO mice recapitulate the pathophysiology of TRESK mutations in humans. Although we have elucidated the mechanisms through which de novo TRESK dysfunction causes migraine in humans, we still don't know why ubiquitous loss of TRESK differentially affects TG and DRG neurons; whether changes of TRESK activity contribute to episodic and chronic migraines in general populations. In this project we propose to employ a multidisciplinary approach to address these knowledge gaps. First, we will investigate the mechanisms through which TRESK dysfunction differentially affects TG and DRG neurons. We will identify transcriptional regulatory proteins that selectively upregulate TRPV1 expression in KO TG neurons. We will also identify the ion channel(s) that compensate for the loss of TRESK activity in DRG neurons. Secondly, based on our preliminary finding that changes of endogenous TRESK activity correlates with changes of the excitability of TG neurons during estrous cycles in female mice, we will test the hypothesis that estrogen increases migraine susceptibility in women through inhibition of endogenous TRESK activity in TG neurons. Finally, we will test the hypothesis that frequent migraine attacks reduce TG TRESK currents, thereby increasing the risk of migraine chronification. We will investigate how endogenous TRESK activity is affected in a mouse model of chronic migraine; and whether altering TRESK activity in TG neurons is sufficient to modify the process of migraine chronification. Collectively, results from these studies will elucidate novel mechanisms through which TRESK differentially regulates the neuronal circuits encoding trigeminal and body pain. This will ultimately leads to better understanding of the physiology and pathophysiology of both systems.

与TWIK相关的脊髓K+（TRESK）通道在所有主要传入神经元中均大量表达 （pan）在三叉神经节（TG）和背根神经节（DRG）中，介导背景K+电流和 控制平底锅的兴奋性。但是，特雷斯克突变会导致偏头痛，但不会导致身体疼痛 人类，表明TG神经元比DRG神经元更容易受到TRESK功能障碍的影响。我们 发现与偏头痛相关的TRESK突变导致Tresk蛋白的截断，这 对内源性TRESK电流产生强大的显性阴性作用。这促使我们使用Tresk 敲除（KO）小鼠作为模型系统，研究TRESK活动对疼痛的影响 传播。尽管所有锅中的Tresk电流无处不在，但只有一个亚群TG神经元 在Tresk中，KO小鼠变得高度启动。出乎意料的是，辣椒素反应性神经元的百分比 在TG中有选择地增加KO小鼠的DRG。 Tresk KO小鼠表现出更强大的行为 反应比野生型对照在三叉神经疼痛的小鼠模型中，尤其是头痛。相反，野性 类型和KO小鼠对后爪上有害刺激的反应类似。这些结果表明TRESK KO 小鼠概括了人类TRESK突变的病理生理学。 尽管我们已经阐明了从头tresk功能障碍引起偏头痛的机制 在人类中，我们仍然不知道为什么Tresk无处不在的损失会影响TG和DRG神经元。 TRESK活动的变化是否有助于一般人群中的情节性和慢性偏头痛。在这个 我们建议采用多学科方法来解决这些知识差距。首先，我们会的 研究TRESK功能障碍差异影响TG和DRG神经元的机制。我们 将识别转录调节蛋白在KO TG神经元中有选择地上调TRPV1表达。 我们还将确定弥补DRG神经元中TRESK活性损失的离子通道。 其次，基于我们的初步发现，内源性TRESK活动的变化与 雌性小鼠发情过程中TG神经元兴奋性的变化，我们将检验以下假设。 雌激素通过抑制TG中内源性TRESK活性来增加女性的偏头痛易感性 神经元。最后，我们将检验以下假设：频繁偏头痛攻击减少TG Tresk电流，从而 增加偏头痛的风险。我们将研究内源性TRESK活性如何影响 慢性偏头痛的小鼠模型；以及TG神经元中的TRESK活性是否足以修饰 偏头痛的过程。 总的来说，这些研究的结果将阐明新机制，通过这些机制差异化 调节编码三叉神经和身体疼痛的神经元电路。这最终将导致更好 了解这两种系统的生理和病理生理学。