Oka Masumi, Akaki Sohta, Ohno Osamu, Terasaki Maho, Hamaoka-Tamura Yuho, Saito Michiko, Kato Shinichi, Inoue Asuka, Aoki Junken, Matsuno Kenji, Furuta Kazuyuki, Tanaka Satoshi
Laboratory of Pharmacology, Division of Pathological Sciences (M.O., M.T., Y.H.-T., S.T.), Bioscience Research Center (M.S.), and Laboratory of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences (S.K.), Kyoto Pharmaceutical University, Kyoto, Japan; Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (S.A., K.F.); Laboratory of Medicinal Chemistry, Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, Tokyo, Japan (O.O.); Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (A.I.); Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (J.A.); and Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan (K.M.).
Laboratory of Pharmacology, Division of Pathological Sciences (M.O., M.T., Y.H.-T., S.T.), Bioscience Research Center (M.S.), and Laboratory of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences (S.K.), Kyoto Pharmaceutical University, Kyoto, Japan; Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (S.A., K.F.); Laboratory of Medicinal Chemistry, Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, Tokyo, Japan (O.O.); Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (A.I.); Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (J.A.); and Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan (K.M.)
J Pharmacol Exp Ther. 2024 Mar 15;389(1):76-86. doi: 10.1124/jpet.123.002024.
Mast cell stabilizers, including disodium cromoglycate (DSCG), were found to have potential as the agonists of an orphan G protein-coupled receptor, GPR35, although it remains to be determined whether GPR35 is expressed in mast cells and involved in suppression of mast cell degranulation. Our purpose in this study is to verify the expression of GPR35 in mast cells and to clarify how GPR35 modulates the degranulation. We explored the roles of GPR35 using an expression system, a mast cell line constitutively expressing rat GPR35, peritoneal mast cells, and bone marrow-derived cultured mast cells. Immediate allergic responses were assessed using the IgE-mediated passive cutaneous anaphylaxis (PCA) model. Various known GPR35 agonists, including DSCG and newly designed compounds, suppressed IgE-mediated degranulation. GPR35 was expressed in mature mast cells but not in immature bone marrow-derived cultured mast cells and the rat mast cell line. Degranulation induced by antigens was significantly downmodulated in the mast cell line stably expressing GPR35. A GPR35 agonist, zaprinast, induced a transient activation of RhoA and a transient decrease in the amount of filamentous actin. GPR35 agonists suppressed the PCA responses in the wild-type mice but not in the GPR35 mice. These findings suggest that GPR35 should prevent mast cells from undergoing degranulation induced by IgE-mediated antigen stimulation and be the primary target of mast cell stabilizers. SIGNIFICANCE STATEMENT: The agonists of an orphan G protein-coupled receptor, GPR35, including disodium cromoglycate, were found to suppress degranulation of rat and mouse mature mast cells, and their antiallergic effects were abrogated in the GPR35 mice, indicating that the primary target of mast cell stabilizers should be GPR35.
肥大细胞稳定剂，包括色甘酸二钠（DSCG），被发现有可能作为一种孤儿G蛋白偶联受体GPR35的激动剂，尽管GPR35是否在肥大细胞中表达并参与抑制肥大细胞脱颗粒仍有待确定。本研究的目的是验证GPR35在肥大细胞中的表达，并阐明GPR35如何调节脱颗粒。我们使用表达系统、组成性表达大鼠GPR35的肥大细胞系、腹膜肥大细胞和骨髓来源的培养肥大细胞来探究GPR35的作用。使用IgE介导的被动皮肤过敏反应（PCA）模型评估即刻过敏反应。包括DSCG和新设计的化合物在内的各种已知GPR35激动剂均抑制了IgE介导的脱颗粒。GPR35在成熟肥大细胞中表达，但在未成熟的骨髓来源培养肥大细胞和大鼠肥大细胞系中不表达。在稳定表达GPR35的肥大细胞系中，抗原诱导的脱颗粒明显下调。GPR35激动剂扎普司特诱导RhoA的瞬时激活和丝状肌动蛋白量的瞬时减少。GPR35激动剂抑制野生型小鼠的PCA反应，但不抑制GPR35基因敲除小鼠的反应。这些发现表明，GPR35可防止肥大细胞在IgE介导的抗原刺激下发生脱颗粒，并且是肥大细胞稳定剂的主要靶点。重要声明：包括色甘酸二钠在内的孤儿G蛋白偶联受体GPR35的激动剂被发现可抑制大鼠和小鼠成熟肥大细胞的脱颗粒，并且它们的抗过敏作用在GPR35基因敲除小鼠中被消除，这表明肥大细胞稳定剂的主要靶点应该是GPR35。
