Inflammatory hyperalgesia due to TRPV1, the pepper spray receptor in the cornea

TRPV1（角膜中的胡椒喷雾受体）引起的炎症性痛觉过敏

• 批准号: 9982957
• 负责人: Sharona E Gordon
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982957
• 关键词: Acute inflammatory pain; Address; Afferent Neurons; Ankyrin Repeat; Binding; Bypass; Capsicum; Cations; Cell membrane; Cells; Chemicals; Chemosensitization; Complex; Cornea; Data; Enzyme Activation; Exocytosis; Goals; Hyperalgesia; Inflammation; Inflammation Mediators; Inflammatory; Ion Channel; Lipids; Measurement; Measures; Membrane; Modeling; Molecular; Molecular Conformation; Molecular Probes; Nerve Growth Factors; Neurons; Opioid; Pain; Pathway interactions; Peripheral Nervous System; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Physiology; Play; Production; Regulation; Role; Shapes; Signal Transduction; Stimulus; Surface; System; TRP channel; Testing; Thermal Hyperalgesias; Vanilloid; Vesicle; aging population; base; fluorescence imaging; in vitro Assay; in vivo; inflammatory pain; novel; optogenetics; pain receptor; pain relief; pain signal; particle; phyA phytochrome; receptor; response; single molecule; tool; trafficking

TRPV1 ion channels play a critical role in the increase in sensitivity to pain that occurs in the setting of inflammation in the cornea and throughout the peripheral nervous system. We address the cellular and molecular mechanisms by which one of the most important inflammatory mediators, nerve growth factor (NGF), triggers trafficking of TRPV1 to the plasma membrane. We have previously shown that NGF increases the number of TRPV1 channels in the plasma membrane of sensory neurons via activation of the enzyme phosphoinositide 3-kinase (PI3K, Class IA), which phosphorylates the signaling lipid phosphoinositide 4,5-bisphosphate (PIP2) to make phosphoinositide 3,4,5-trisphosphate (PIP3) (Figure 1A). PIP3 is a ubiquitous signal for membrane trafficking, and causes TRPV1-laden vesicles to fuse with the plasma membrane via regulated exocytosis. This enhanced trafficking is facilitated by a direct interaction among the Ankyrin Repeat Domain (ARD) of TRPV1 and the p85 regulatory subunit of PI3K (Figure 1B). The major preliminary finding upon which this renewal proposal is based is that the interaction between TRPV1 and PI3K potentiates NGF-stimulated activation of PI3K. This proposal will leverage our preliminary data to investigate the physiology and mechanism by which this occurs.

TRPV 1离子通道在疼痛敏感性增加中起着关键作用，疼痛敏感性增加发生在以下情况中： 角膜和周围神经系统的炎症。我们解决了细胞和 神经生长因子是最重要的炎症介质之一， (NGF)，触发TRPV 1向质膜的运输。我们之前已经证明， 通过酶的激活，感觉神经元质膜中TRPV 1通道的数量 磷酸肌醇3-激酶（PI 3 K，IA类），其磷酸化信号脂质磷酸肌醇 在一个实施方案中，将磷酸肌醇3，4，5-二磷酸（PIP 2）转化为磷酸肌醇3，4，5-三磷酸（PIP 3）（图1A）。PIP 3是一种无处不在的 信号膜运输，并导致TRPV 1负载囊泡融合与质膜通过 调节胞吐作用。安克林重复组织之间的直接互动促进了这种更大的贩运 TRPV 1的ARD结构域和PI 3 K的p85调节亚基（图1B）。主要的初步发现 该更新建议所基于的是TRPV 1和PI 3 K之间的相互作用增强了NGF刺激的PI 3 K活化。该提案将利用我们的初步数据来研究生理学， 这种情况发生的机制。