Nothacker H P, Wang Z, Zhu Y, Reinscheid R K, Lin S H, Civelli O
Department of Pharmacology, University of California at Irvine, Irvine, California, USA.
Mol Pharmacol. 2000 Dec;58(6):1601-8. doi: 10.1124/mol.58.6.1601.
The cysteinyl leukotrienes (CysLTs) are potent biological mediators in the pathophysiology of inflammatory diseases, in particular of airway obstruction in asthma. Pharmacological studies have suggested the existence of at least two types of CysLT receptors, designated CysLT(1) and CysLT(2). The CysLT(1) receptor has been cloned recently. Here we report the molecular cloning, expression, localization, and functional characterization of a human G protein-coupled receptor that has the expected characteristics of a CysLT(2) receptor. This new receptor is selectively activated by nanomolar concentrations of CysLTs with a rank order potency of LTC(4) = LTD(4) >> LTE(4). The leukotriene analog BAY u9773, reported to be a dual CysLT(1)/CysLT(2) antagonist, was found to be an antagonist at CysLT(1) sites but acted as a partial agonist at this new receptor. The structurally different CysLT(1) receptor-selective antagonists zafirlukast, montelukast, and MK-571 did not inhibit the agonist-mediated calcium mobilization of CysLT(2) receptors at physiological concentrations. Localization studies indicate highest expression of CysLT(2) receptors in adrenal glands, heart, and placenta; moderate levels in spleen, peripheral blood leukocytes, and lymph nodes; and low levels in the central nervous system and pituitary. The human CysLT(2) receptor gene is located on chromosome 13q14.12-21.1. The new receptor exhibits all characteristics of the thus far poorly defined CysLT(2) receptor. Moreover, we have identified BAY u9773 as a CysLT(2) selective agonist, which could prove to be of immediate use in understanding the functional roles of the CysLT(2) receptor.
半胱氨酰白三烯(CysLTs)是炎症性疾病病理生理学中的强效生物介质,尤其是在哮喘气道阻塞方面。药理学研究表明至少存在两种类型的CysLT受体,分别命名为CysLT(1)和CysLT(2)。CysLT(1)受体最近已被克隆。在此,我们报告一种人类G蛋白偶联受体的分子克隆、表达、定位及功能特性,该受体具有CysLT(2)受体的预期特征。这种新受体被纳摩尔浓度的CysLTs选择性激活,其效力顺序为LTC(4)=LTD(4)>>LTE(4)。白三烯类似物BAY u9773据报道是一种双重CysLT(1)/CysLT(2)拮抗剂,结果发现它在CysLT(1)位点是拮抗剂,但在这种新受体上起部分激动剂的作用。结构不同的CysLT(1)受体选择性拮抗剂扎鲁司特、孟鲁司特和MK-571在生理浓度下不抑制激动剂介导的CysLT(2)受体钙动员。定位研究表明CysLT(2)受体在肾上腺、心脏和胎盘中表达最高;在脾脏、外周血白细胞和淋巴结中表达中等;在中枢神经系统和垂体中表达较低。人类CysLT(2)受体基因位于13号染色体q14.12-21.1区域。这种新受体展现出了迄今为止定义尚不明确的CysLT(2)受体的所有特征。此外,我们已确定BAY u9773为CysLT(2)选择性激动剂,这可能会立即有助于理解CysLT(2)受体的功能作用。