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Regulation of Trigeminal Nociception by TRESK Channels

TRESK 通道对三叉神经伤害感受的调节

基本信息

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
项目类别：
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

项目摘要

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.

twik相关的脊髓K+ (TRESK)通道在所有初级传入神经元中大量表达