Prostaglandin E2 EP receptor trafficking and nociception

许多药物或化合物通过与细胞表面自身受体结合并触发随后的细胞内信号传导事件来诱导细胞内的生物功能。为应对环境变化，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）是炎症组织中大量产生的疼痛介质。PGE2通过其存在于疼痛诱导神经细胞（痛觉感受器）中的EP受体，直接刺激痛觉感受器并刺激这些细胞释放引起疼痛的肽，从而引起疼痛。EP1和EP2定位于细胞表面和细胞内池，EP3和EP4主要定位于细胞内。疼痛状态可改变EP受体的离散亚细胞分布，这表明PGE2能够诱导其受体往返于细胞表面，从而结合或多或少的PGE2，从而增强或抑制疼痛反应。事实上，我们还观察到PGE2增加了EP4受体在培养的疼痛诱导神经细胞中的细胞表面表达，这些细胞通常储存在细胞内池中。基于这些数据，我们假设PGE2诱导EP4受体转运到伤害感受器的细胞表面，从而增强疼痛反应。已经制定了一个研究计划来验证这一假设。在本研究计划的初始阶段，我们将着眼于EP4在静止和刺激状态下进出细胞表面的运输，以及它在PGE2诱导的疼痛肽释放中的作用。本研究计划的意义在于缩小我们对EP受体转运及其在调节PGE2诱导疼痛中的作用的理解的知识差距。了解痛觉感受器中EP受体运输的机制及其在PGE2诱导疼痛中的作用，将有可能为治疗PGE2/EP受体信号参与的各种疼痛状况开辟新的治疗途径。

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.