Prostaglandin E2 EP receptor trafficking and nociception

许多药物或化合物通过与细胞表面的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学功能。在对环境变化的响应中，通过其运输改变细胞表面的受体密度是调节受体诱导的细胞功能的关键机制。前列腺素E2（PGE 2）是一种众所周知的疼痛介质，在炎症组织中大量产生。PGE 2通过其存在于疼痛诱导神经细胞（伤害感受器）中的EP受体，通过直接刺激伤害感受器和通过刺激从这些细胞释放引起疼痛的肽来引起疼痛。四种EP受体位于伤害感受器的离散亚细胞结构域中，其中EP 1和EP 2定位于细胞表面以及细胞内池中，而EP 3和EP 4主要位于细胞内。EP受体的离散亚细胞分布可通过疼痛状态改变，表明PGE 2能够诱导其受体运输至细胞表面和从细胞表面运输，从而结合更多或更少的PGE 2，从而增强或抑制疼痛反应。事实上，我们还观察到PGE 2增加了培养的疼痛诱导神经细胞中EP 4受体的细胞表面表达，其通常储存在细胞内库中。基于这些数据，我们因此假设PGE 2诱导EP 4受体运输到伤害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验证这一假设。在本研究计划的初始阶段，我们将针对静止和刺激状态下EP 4往返细胞表面的运输，及其在PGE 2诱导的疼痛肽释放中的作用。这项研究计划的意义在于缩小我们对EP受体运输及其在调节PGE 2诱导的疼痛中的作用的理解的知识差距。了解EP受体在伤害感受器中的运输机制及其在PGE 2诱导的疼痛中的作用，将可能为治疗涉及PGE 2/EP受体信号传导的各种疼痛病症开辟新的治疗途径。

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.