Prostanoid Receptors
Prostanoid Receptors
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DOI：
10.1111/j.1749-6632.1994.tb52729.x
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发表时间：
1994-11
影响因子：
5.2
通讯作者：
S. Narumiya
中科院分区：
文献类型：
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作者：
S. Narumiya
前列腺素包括前列腺素(PGs)和血栓素A(TXs)，在各种细胞和组织中表现出广泛的作用，以维持体内局部的动态平衡。通过比较不同类型前列腺素在不同生物测定系统中的作用和潜力，以及通过检测不同前列腺素类似物在这些系统中的作用，首先从药理学上对介导这些作用的前列腺素受体进行了表征。通过这些研究表明，每个前列腺素都有一个特定的受体，E系列的前列腺素可能有几个受体亚型。通过分析PG诱导的细胞内信号转导，还研究了PG受体与放射性标记的PGs及其类似物的配体结合活性。这些分析表明，PG受体是一种通过G蛋白与腺苷环化酶和磷脂酶C等效应物偶联的受体。然而，直到我们从人的血小板膜上提纯了TXA2/PGH2受体并克隆了其基因，这些受体才被纯化或克隆。这些研究表明，TXA‘受体确实是一种具有七个跨膜区的G蛋白偶联的视紫红质受体，它与视紫红质类型受体的其他成员，如肾上腺素能和毒扁豆碱受体的同源性非常有限。这些结果表明，TXA‘受体属于视紫红质受体超家族中的一个新的亚家族，具有同源结构的前列腺素受体作为一个整体构成了这个亚家族。基于这一假设，我们在不同的cDNA文库中进行了同源性筛选，并克隆了前列腺素受体的几种类型和亚型。这些包括小鼠的TXA受体：小鼠的PGE受体EP1、EP2和EP3亚型，以及小鼠的PGF受体8和小鼠的PGI受体。我们还发现，EP3受体基因经过选择性剪接产生了几个ISOF 0 m 1 S。L~‘我们还鉴定了人的血栓素A’受体基因，并揭示了它的组织化。这些研究不仅阐明了前列腺素受体的分子结构，而且使我们能够在一个分离的系统中研究它们的性质。他们还提供了有关其表达的组织和细胞分布的信息。基于这种分布，新的前列腺素作用已被研究和重新认识。
Prostanoids including prostaglandins (PGs) and thromboxanes (TXs) exhibit a wide variety of actions in various cells and tissues to maintain local homeostasis in the body. Characterization of the prostanoid receptors mediating these actions was carried out first pharmacologically by comparing effects and potencies of various types of PGs in different bioassay systems and by examining the effects of various PG analogues in these systems. Through these studies it was suggested that each prostanoid has a specific receptor and that there may be several receptor subtypes for the PGs of the E series.’ PG receptors were characterized also biochemically as ligandbinding activities of radiolabeled PGs and their analogues, and by analyzing PGinduced signal transduction in cells. These analyses suggested that the PG receptor is a receptor coupling via a G protein to effectors such as adenylate cyclase and phospholipase C . However, none of the receptors was purified or cloned until we purified the TXA2/PGH2 receptor from human blood platelets’ and cloned its cDNA.~ These studies demonstrated that the TXA’ receptor is indeed a G protein-coupled rhodopsin-type receptor with seven transmembrane domains and that it showed a very limited homology to other members of the rhodopsin-type receptors such as adrenergic and muscarinic receptors. These results suggest that the TXA’ receptor belongs to a new subfamily of the rhodopsin superfamily of receptors and that the prostanoid receptors having homologous structures as a whole constitute this subfamily. Based on this assumption, we performed homology screening in various cDNA libraries and cloned several types and subtypes of the prostanoid receptors. These include the mouse TXA’ receptor: the mouse PGE receptor EP1, EP2, and EP3 subtypes,’-’ the mouse PGF receptor,8 and the mouse PGI receptor.’ We also found that the EP3 receptor mRNA undergoes alternative splicing to produce several isof 0 m 1 s . l ~ ’ ~ We also identified the human gene of the TXA’ receptor, and revealed its ~rganization.’~ These studies not only elucidated molecular structures of the prostanoid receptors, but also enabled us to study their properties in an isolated system. They also provided information on tissue and cell distribution of their expression. Based on such distribution, novel prostanoid actions have been examined and re~ea1ed.l~