Uwamizu Akiharu, Inoue Asuka, Suzuki Kensuke, Okudaira Michiyo, Shuto Akira, Shinjo Yuji, Ishiguro Jun, Makide Kumiko, Ikubo Masaya, Nakamura Sho, Jung Sejin, Sayama Misa, Otani Yuko, Ohwada Tomohiko, Aoki Junken
Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; PRESTO, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan; Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and CREST, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan.
Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; PRESTO, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan; Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and CREST, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; PRESTO, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan; Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and CREST, Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan.
J Biochem. 2015 Mar;157(3):151-60. doi: 10.1093/jb/mvu060. Epub 2014 Oct 14.
Lysophosphatidylserine (1-oleoyl-2 R-lysophosphatidylserine, LysoPS) has been shown to have lipid mediator-like actions such as stimulation of mast cell degranulation and suppression of T lymphocyte proliferation, although the mechanisms of LysoPS actions have been elusive. Recently, three G protein-coupled receptors (LPS1/GPR34, LPS2/P2Y10 and LPS3/GPR174) were found to react specifically with LysoPS, raising the possibility that LysoPS serves as a lipid mediator that exerts its role through these receptors. Previously, we chemically synthesized a number of LysoPS analogues and evaluated them as agonists for mast-cell degranulation. Here, we used a transforming growth factor-α (TGFα) shedding assay to see if these LysoPS analogues activated the three LysoPS receptors. Modification of the serine moiety significantly reduced the ability of the analogues to activate the three LysoPS receptors, whereas modification of other parts resulted in loss of activity in receptor-specific manner. We found that introduction of methyl group to serine moiety (1-oleoyl-lysophosphatidylallothreonine) and removal of sn-2 hydroxyl group (1-oleoyl-2-deoxy-LysoPS) resulted in reduction of reactivity with LPS1 and LPS3, respectively. Accordingly, we synthesized a LysoPS analogue with the two modifications (1-oleoyl-2-deoxy-lysophosphatidylallothreonine) and found it to be an LPS2-selective agonist. These pharmacological tools will definitely help to identify the biological roles of these LysoPS receptors.
溶血磷脂酰丝氨酸（1-油酰基-2R-溶血磷脂酰丝氨酸，LysoPS）已被证明具有类似脂质介质的作用，如刺激肥大细胞脱颗粒和抑制T淋巴细胞增殖，尽管LysoPS作用的机制尚不清楚。最近，发现三种G蛋白偶联受体（LPS1/GPR34、LPS2/P2Y10和LPS3/GPR174）与LysoPS特异性反应，这增加了LysoPS作为一种通过这些受体发挥作用的脂质介质的可能性。此前，我们化学合成了多种LysoPS类似物，并将它们作为肥大细胞脱颗粒的激动剂进行了评估。在这里，我们使用转化生长因子-α（TGFα）释放试验来观察这些LysoPS类似物是否激活了三种LysoPS受体。丝氨酸部分的修饰显著降低了类似物激活三种LysoPS受体的能力，而其他部分的修饰则导致受体特异性的活性丧失。我们发现，在丝氨酸部分引入甲基（1-油酰基-溶血磷脂酰别苏氨酸）和去除sn-2羟基（1-油酰基-2-脱氧-LysoPS）分别导致与LPS1和LPS3的反应性降低。因此，我们合成了一种具有这两种修饰的LysoPS类似物（1-油酰基-2-脱氧-溶血磷脂酰别苏氨酸），发现它是一种LPS2选择性激动剂。这些药理学工具肯定有助于确定这些LysoPS受体的生物学作用。
