Takasaki J, Kamohara M, Matsumoto M, Saito T, Sugimoto T, Ohishi T, Ishii H, Ota T, Nishikawa T, Kawai Y, Masuho Y, Isogai T, Suzuki Y, Sugano S, Furuichi K
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
Biochem Biophys Res Commun. 2000 Aug 2;274(2):316-22. doi: 10.1006/bbrc.2000.3140.
Cysteinyl leukotrienes (CysLTs), slow-reacting substances of anaphylaxis, are lipid mediators known to possess potent proinflammatory action. Pharmacological studies using CysLTs indicate that at least two classes of G protein-coupled receptors (GPCRs), named CysLT(1) and CysLT(2), exist; the former is sensitive and the latter is resistant to the CysLT(1) antagonists currently used to treat asthma. Although the CysLT(1) receptor gene has been recently cloned, the molecular identity of the CysLT(2) receptor has remained elusive. Here we show that the pharmacological profile of an orphan GPCR (PSEC0146) is consistent with that of the CysLT(2) receptor. In human embryonic kidney 293 cells that express the PSEC0146 cDNA, leukotriene C(4) (LTC(4)) and leukotriene D(4) (LTD(4)) induce equal increases in intracellular calcium mobilization; these increases are not affected by CysLT(1) antagonists. Additionally, [(3)H]LTC(4) specifically binds to membranes from COS-1 cells transiently transfected with PSEC0146. Large amounts of the PSEC0146 mRNA are found in human heart, placenta, spleen, and peripheral blood leukocytes but not in the lung and the trachea. Pharmacological feature and expression studies will eventually lead to a better understanding of the classification of CysLT receptors, possibly leading to a reconsideration of the pathological and physiological role of CysLTs.
半胱氨酰白三烯（CysLTs），即过敏反应迟缓反应物质，是一类已知具有强大促炎作用的脂质介质。使用CysLTs的药理学研究表明，至少存在两类G蛋白偶联受体（GPCRs），分别命名为CysLT(1)和CysLT(2)；前者对目前用于治疗哮喘的CysLT(1)拮抗剂敏感，后者则具有抗性。尽管CysLT(1)受体基因最近已被克隆，但CysLT(2)受体的分子身份仍然不明。在此我们表明，一个孤儿GPCR（PSEC0146）的药理学特征与CysLT(2)受体相符。在表达PSEC0146 cDNA的人胚肾293细胞中，白三烯C4（LTC(4)）和白三烯D4（LTD(4)）可同等程度地诱导细胞内钙动员增加；这些增加不受CysLT(1)拮抗剂的影响。此外，[(3)H]LTC(4)特异性结合于用PSEC0146瞬时转染的COS-1细胞膜。在人心脏、胎盘、脾脏和外周血白细胞中发现大量PSEC0146 mRNA，但在肺和气管中未发现。药理学特征和表达研究最终将有助于更好地理解CysLT受体的分类，可能会促使人们重新考虑CysLTs的病理和生理作用。
