Stitham Jeremiah, Arehart Eric J, Gleim Scott R, Douville Karen L, Hwa John
Department of Pharmacology & Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755, USA.
Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):95-108. doi: 10.1016/j.prostaglandins.2006.05.010. Epub 2006 Jul 3.
Prostacyclin (PGI2) is released by vascular endothelial cells and serves as a potent vasodilator, inhibitor of platelet aggregation (anti-thrombotic), and moderator of vascular smooth muscle cell proliferation-migration-differentiation (anti-atherosclerotic). These actions are mediated via a seven transmembrane-spanning G-protein coupled receptor (GPCR), known as the human prostacyclin receptor or hIP. Animal studies using prostacyclin receptor knock-out (IP-/-) mice have revealed increased propensities towards thrombosis, intimal hyperplasia, atherosclerosis, restenosis, as well as reperfusion injury. Of further importance has been the world-wide withdrawal of selective COX-2 inhibitors, due to their discriminating suppression of COX-2-derived PGI2 and its cardioprotective effects, leading to increased cardiovascular events, including myocardial infarction and thrombotic stroke. Over the last decade, mutagenesis studies of the IP receptor, in conjunction with in vitro functional assays and molecular modeling, have provided critical insights into the molecular mechanisms of both agonist binding and receptor activation. Most recently, the discovery of naturally-occurring and dysfunctional mutations within the hIP has provided additional insights into the proposed cardioprotective role of prostacyclin. The aim of this review is to summarize the most recent findings regarding hIP receptor structure-function that have developed through the study of both synthetic and naturally-occurring mutations.
前列环素（PGI2）由血管内皮细胞释放，是一种强效血管舒张剂、血小板聚集抑制剂（抗血栓形成）以及血管平滑肌细胞增殖 - 迁移 - 分化调节剂（抗动脉粥样硬化）。这些作用是通过一种七跨膜G蛋白偶联受体（GPCR）介导的，该受体称为人前列环素受体或hIP。使用前列环素受体敲除（IP - / -）小鼠的动物研究表明，其血栓形成、内膜增生、动脉粥样硬化、再狭窄以及再灌注损伤的倾向增加。更重要的是，由于选择性COX - 2抑制剂对COX - 2衍生的PGI2及其心脏保护作用的选择性抑制，导致心血管事件增加，包括心肌梗死和血栓性中风，这些药物已在全球范围内撤市。在过去十年中，IP受体的诱变研究，结合体外功能测定和分子建模，为激动剂结合和受体激活的分子机制提供了关键见解。最近，hIP内天然存在的和功能失调的突变的发现，为前列环素提出的心脏保护作用提供了更多见解。本综述的目的是总结通过对合成突变和天然存在的突变的研究而得出的关于hIP受体结构 - 功能的最新发现。
