Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Trends Pharmacol Sci. 2013 Jul;34(7):413-23. doi: 10.1016/j.tips.2013.05.003. Epub 2013 Jun 21.
Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP-PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP-Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor.
针对由环氧化酶-2（COX-2 或 PTGS2）调控的病理状况，特定的前列腺素合酶或受体的调节为治疗提供了非甾体抗炎药（NSAIDs）的替代方案。在 COX-2 的下游信号通路中，前列腺素 E2（PGE2）受体 EP2 亚型（PTGER2）作为许多生理和病理事件的关键介质而出现。遗传消融策略和化学生物学的最新进展为更好地理解 EP2 信号提供了工具。在大脑中，EP2 受体通过 cAMP-PKA 信号调节一些有益的作用，包括在兴奋性毒性、神经可塑性和空间学习的急性模型中的神经保护作用。相反，EP2 的激活通过 cAMP-Epac 途径加重慢性炎症，可能导致迟发性神经毒性。EP2 受体的激活还通过 G 蛋白非依赖性途径使β-arrestin 参与其中，从而促进肿瘤细胞的生长和迁移。了解多个 EP2 信号通路被激活的条件可能会提出针对这种关键炎症性前列腺素受体的新的治疗策略。
