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Prostaglandin E2 EP receptor trafficking and nociception

前列腺素 E2 EP 受体运输和伤害感受

基本信息

批准号：
356021-2011
负责人：
Ma, Weiya
金额：
$ 2.19万
依托单位：
McGill University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2011
资助国家：
加拿大
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=482997
关键词：
Prostaglandin E2 EP receptor trafficking

项目摘要

Numerous drugs or compounds induce biological functions inside the cells by binding to their own receptors at the cell surface and triggering subsequent intracellular signalling events. In response to the environmental changes, altering the receptor density at the cell surface through its trafficking is a key mechanism to modulate receptor induced cell functions. Prostaglandin E2 (PGE2) is a well known pain mediator abundantly produced in inflamed tissues. PGE2 causes pain through its EP receptors present in pain inducing nerve cells (nociceptors) by directly exciting nociceptors and by stimulating the release of pain causing peptides from these cells. Four EP receptors are located in discrete subcellular domains of nociceptors, with EP1 and EP2 localizing at the cell surface as well as in the intracellular pool while EP3 and EP4 being mainly intracellular. The discrete subcellular distribution of EP receptors is modifiable by pain states, suggesting that PGE2 is able to induce its receptor trafficking to and from the cell surface, thus binding more or fewer PGE2 and consequently enhancing or suppressing pain response. Indeed we also observed that that PGE2 increases the cell surface expression of EP4 receptors in cultured pain inducing nerve cells, which is normally stored in an intracellular pool. Based on these data, we hence hypothesize that PGE2 induces EP4 receptor trafficking to the cell surface of nociceptors to enhance pain response. A research program has been formulated to test this hypothesis. At the initial stage of this research program, we will aim at EP4 trafficking to and from the cell surface at rest and stimulated states, and its role in PGE2 induced pain peptide release. The significance of this research program is to narrow the knowledge gap in our understanding of EP receptor trafficking and its role in modulating PGE2 induced pain. Understanding the mechanisms governing EP receptor trafficking in nociceptors and its role in PGE2 induced pain will potentially open a novel therapeutic avenue to treat various pain conditions in which PGE2/EP receptor signalling is involved.

许多药物或化合物通过与细胞表面它们自己的受体结合并触发随后的细胞内信号事件来诱导细胞内的生物功能。作为对环境变化的响应，通过转运改变细胞表面受体密度是调节受体诱导细胞功能的关键机制。前列腺素E2(PGE2)是一种广为人知的疼痛介质，在炎症组织中大量产生。PGE2通过存在于疼痛诱导神经细胞(伤害性感受器)中的EP受体，通过直接刺激伤害性感受器和刺激这些细胞释放引起疼痛的多肽来产生疼痛。4种EP受体定位于伤害性感受器的亚细胞区，EP1和EP2定位于细胞表面和胞内池，EP3和EP4主要定位于细胞内。EP受体的离散亚细胞分布可以被疼痛状态改变，这表明PGE2能够诱导其受体往返于细胞表面，从而与或多或少的PGE2结合，从而增强或抑制疼痛反应。事实上，我们还观察到，PGE2增加了培养的痛觉诱导神经细胞中EP4受体的细胞表面表达，而这些细胞通常储存在细胞内的池中。基于这些数据，我们因此假设PGE2诱导EP4受体转运到伤害性感受器的细胞表面以增强疼痛反应。已经制定了一项研究计划来检验这一假设。在这项研究计划的初始阶段，我们将致力于研究EP4在静止和刺激状态下往返于细胞表面的运输，以及它在PGE2诱导的痛肽释放中的作用。这项研究的意义在于缩小我们对EP受体转运及其在调节PGE2诱导的疼痛中的作用的认识上的差距。了解伤害性感受器中EP受体转运的机制及其在PGE2诱导的疼痛中的作用，可能会为治疗涉及PGE2/EP受体信号的各种疼痛开辟一条新的治疗途径。