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: 10414845
• 负责人: Sharona E Gordon
• 金额: $ 10.66万
• 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/10414845
• 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.

TRPV1离子通道在痛觉敏感度的增加中起关键作用 角膜和整个周围神经系统的炎症。我们解决了蜂窝和 最重要的炎症介质之一神经生长因子的分子机制 (NGF)，触发TRPV1向质膜的运输。我们之前已经证明，NGF会增加 酶激活感觉神经元质膜上TRPV1通道的数目 磷脂酰肌醇3-激酶(PI3K，IA类)，可磷酸化信号脂质磷脂酰肌醇 4，5-二磷酸(PIP2)生成3，4，5-三磷酸(PIP3)(图1A)。PIP3是一个无处不在的 膜转运的信号，并导致携带TRPV1的囊泡通过 有规律的胞吐作用。Ankyrin重复序列之间的直接相互作用促进了这种增强的贩运 TRPV1的结构域(ARD)和PI3K的P85调节亚基(图1B)。主要的初步发现 这一更新建议的基础是TRPV1和PI3K之间的相互作用增强了NGF刺激的PI3K的激活。这项建议将利用我们的初步数据来研究生理学和 发生这种情况的机制。