Function and regulation of acid-sensing ion channels in corneal neurons

角膜神经元酸敏离子通道的功能和调节

• 批准号: 9395287
• 负责人: John Bankston
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395287
• 关键词: ASIC channel; Acidosis; Acids; Afferent Neurons; Alternative Splicing; Biological Models; Bradykinin; Calcium; Cell Surface Receptors; Cell membrane; Cell surface; Chemicals; Cornea; Corneal pain; Development; Dinoprostone; Disease; Esthesia; Eye; Eye Injuries; Family; G-Protein-Coupled Receptors; Genes; Goals; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Ion Channel; Irritants; Ischemia; Kinins; Label; Lipids; Measures; Mechanics; Mediating; Membrane; Metals; Molecular; Mus; Nerve; Nerve Endings; Neurons; Nociception; Pain; Pain management; Pathologic; Pathway interactions; Phosphatidylinositols; Phospholipase C Signaling Pathway; Phosphoric Monoester Hydrolases; Play; Polyamines; Preparation; Process; Prostaglandins; Protein Isoforms; Protons; Pruritus; Receptor Protein-Tyrosine Kinases; Regulation; Role; Sensory; Signal Transduction; Signaling Molecule; Sodium; Stimulus; Structure; Structure of trigeminal ganglion; Suggestion; Temperature; Testing; Tissues; Toxin; Work; Wound Healing; blink reflexes; epithelial Na+ channel; injured; lacrimal; mechanical force; ocular pain; ocular surface; receptor; response; sensor; tool; trafficking; tumor growth; voltage

Nociception, the process through which a subset of sensory neurons detects noxious (painful) stimuli, is an important but poorly understood process in the trigeminal ganglion neurons that innervate the cornea. These neurons respond to a wide array of irritating stimuli including heat, cooling, mechanical force, and chemicals including protons and inflammatory molecules. Inflammation in the cornea, a result of damage to the neurons that innervate it, often leads to sensitization of those neurons. The response to noxious stimuli and to inflammatory molecules is mediated in large part by ion channels, G-protein coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs). A better understanding of the ion channels involved in ocular pain and the hyperalgesic sensory pathway would be important for development of more targeted pain management tools. It has been long known that the cornea displays a strong response to pH, but until recently, it was not known what molecule is responsible for sensing acidification. New work has identified the acid-sensing ion channels (ASICs) as the primary pH sensor. Moreover, there has been some suggestion that these channels can be sensitized in response to inflammation. The goal of this work is to understand the cellular and molecular mechanisms by which GPCRs and RTKs regulate the function, trafficking, and expression of acid-sensing on channels during pain transduction. To do this, I will record electrical signals from both from isolated corneal nerves and intact nerve terminals. I will measure the ion channels response to pro-inflammatory molecules like kinins and prostaglandins. Many of these inflammatory molecules trigger the activation of the phospholipase c signaling pathway, which reduces the amount of the phosphoinositide, PI(4,5)P2, in the membrane. Change in PI(4,5)P2 has been shown to sensitize other channels to stimulation and I hypothesize that the same is happening for ASICs. Thus, I will examine the role that regulation of phosphoinositides play in corneal neurons and in the function of ASICs.

伤害感，一部分感觉神经元通过这个过程检测到伤害性的(痛苦的) 刺激是三叉神经节神经元中一个重要但知之甚少的过程 支配角膜。这些神经元对包括热在内的一系列刺激性刺激做出反应， 冷却、机械力和包括质子和炎症分子在内的化学物质。 角膜中的炎症是由于支配它的神经元受损而导致的，通常会导致 这些神经元的敏感化。对有害刺激和炎症分子的反应是 主要由离子通道、G蛋白偶联受体(GPCRs)和受体介导 酪氨酸激酶(RTK)。更好地了解离子通道参与眼痛和 痛觉过敏的感觉通路对于发展更有针对性的疼痛是很重要的。 管理工具。人们很早就知道角膜对pH值有很强的反应，但是 直到最近，人们还不知道是什么分子负责感知酸化。新作品 已确定酸敏离子通道(ASIC)是主要的pH传感器。此外，还有 有一些迹象表明，这些通道可以被致敏，以应对炎症。 这项工作的目标是了解GPCRs的细胞和分子机制 RTK调控细胞膜上酸感的功能、运输和表达 疼痛传导。为了做到这一点，我将记录来自分离的角膜神经的电信号 和完整的神经末梢。我会测量离子通道对促炎的反应 激动素和前列腺素等分子。这些炎症分子中的许多会触发 激活磷脂酶c信号通路，从而减少 磷脂酰肌醇，PI(4，5)P2。PI(4，5)P2的变化已被证明是敏感的 其他刺激渠道，我假设同样的情况也发生在ASIC身上。因此，我会 研究磷脂酰肌醇在角膜神经元中的调节作用及其在功能中的作用 ASIC。