title: Lysophosphatidylserine analogues differentially activate three LysoPS receptors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Uwamizu
authors.affiliation: 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.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Okudaira
authors.affiliation: 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.
authors.forename: Akira
authors.initials: A
authors.lastname: Shuto
authors.affiliation: 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.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shinjo
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishiguro
authors.affiliation: 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.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Makide
authors.affiliation: 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.
authors.forename: Masaya
authors.initials: M
authors.lastname: Ikubo
authors.affiliation: 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.
authors.forename: Sho
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: 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.
authors.forename: Sejin
authors.initials: S
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Misa
authors.initials: M
authors.lastname: Sayama
authors.affiliation: 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.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.affiliation: 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.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
authors.affiliation: 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 jaoki@m.tohoku.ac.jp.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008246:Lysophospholipids / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D049312:Receptors, Lysophospholipid / Q000819:agonists / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: C118065:G-protein-coupled receptor 34; C581018:GPR174 protein, human; D008246:Lysophospholipids; C529547:P2RY10 protein, human; D010718:Phosphatidylserines; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D018048:Receptors, Purinergic P2; D016211:Transforming Growth Factor alpha; C025059:lysophosphatidylserine
keywords: GPCR; TGFα shedding assay; agonist; chemical biology; lysophosphatidylserine