The regulation mechanism of nRTKs activation by ionotropic receptor

• Project/Area Number: 18K14925
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Takasaki University of Health and Welfare
• Principal Investigator: Yoshida Kazuki 高崎健康福祉大学, 薬学部, 助教 (70803154)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: P2受容体 / マスト細胞 / ATP / 非受容体型チロシンキナーゼ / GPCR / P2X受容体

Outline of Final Research Achievements

IgE/Ag dependent mast cell activation is regulated by various receptors. We found that extracellular ATP enhances IgE-dependent mast cell activation via P2X4 receptors. Therefore, we investigated the mechanism of its enhancement and the role of P2X4 receptor on anaphylaxis in vivo. The P2X4 receptor enhanced degranulation by promoting the phosphorylation of Syk by FcεRI. This reaction was considered to be independent of ion channel activity. Furthermore, anaphylactic symptoms were alleviated in P2X4 receptor-deficient mice. These results suggested that P2X4 receptor exacerbates the type I allergic reaction.

Academic Significance and Societal Importance of the Research Achievements

マスト細胞に発現しているP2X4受容体の活性化は抗原依存的なマスト細胞の活性化を促進しており、ヒスタミンや炎症性サイトカインの放出を増加させることが示され、P2X4受容体を欠損したり阻害するとアナフィラキシー症状が緩和することが明らかとなった。即ち、P2X4受容体はマスト細胞によるⅠ型アレルギー反応を増悪させる受容体であることが明らかとなった。さらに、P2X4受容体はPGE2による抗原非依存的マスト細胞の活性化も促進したことから、炎症時におけるマスト細胞の活性化も促進していると考えられた。
これらの結果から、P2X4受容体はアレルギー性疾患における新規治療ターゲットとなりうると考えられた。

Research Products

• [Journal Article] Synergistic Cytokine Production by ATP and PGE2 via P2X4 and EP3 Receptors in Mouse Bone-Marrow-Derived Mast Cells (2022)
  • Author(s): Obayashi Kosuke、Yoshida Kazuki、Ito Masa-aki、Mori Tetsuya、Yamamoto Kimiko、Imai Toshiyashu、Matsuoka Isao
  • Journal Title: Cells Volume: 11 Issue: 4 Pages: 616-616
  • DOI: 10.3390/cells11040616
  • Peer Reviewed / Open Access
• [Journal Article] Elucidation of Mast Cell Activation Mechanism Mediated by Purinergic Signaling (2021)
  • Author(s): Yoshida Kazuki
  • Journal Title: YAKUGAKU ZASSHI Volume: 141 Issue: 9 Pages: 1057-1061
  • DOI: 10.1248/yakushi.21-00113
  • NAID: 130008081765
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2021-09-01
  • Peer Reviewed
• [Journal Article] Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation (2020)
  • Author(s): Yoshida Kazuki、Ito Masa-aki、Sato Naoko、Obayashi Kosuke、Yamamoto Kimiko、Koizumi Schuichi、Tanaka Satoshi、Furuta Kazuyuki、Matsuoka Isao
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 12 Pages: 3077-3085
  • DOI: 10.4049/jimmunol.1900954
  • Peer Reviewed / Open Access
• [Journal Article] Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine Mast Cells (2019)
  • Author(s): Yoshida、Tajima、Nagano、Obayashi、Ito、Yamamoto、Matsuoka
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 20 Pages: 5157-5157
  • DOI: 10.3390/ijms20205157
  • Peer Reviewed / Open Access
• [Presentation] P2X4 receptor signaling potentiate Mas-relate G protein-coupled receptor B2-induced mast cell degranulation (2022)
  • Author(s): Kazuki Yoshida，Kousuke Obayashi，Syouta Tanihara，Yuuki Miyashita，Masa-aki Ito，Isao Matsuoka,
  • Organizer: 第95回日本薬理学会年会
• [Presentation] Upregulation of P2X7 receptor signaling by interleukin-33 in mouse bone marrow-derived mast cells (2021)
  • Author(s): Kazuki Yoshida, Yuu Ishida, Masaaki Ito, Isao Matsuoka
  • Organizer: 第94回日本薬理学会年会
• [Presentation] P2X4受容体が結合組織型マスト細胞の脱顆粒反応に及ぼす影響 (2021)
  • Author(s): 吉田一貴、伊藤政明、松岡功
  • Organizer: 日本薬学会第141年会
• [Presentation] プリン受容体を解するマスト細胞活性化メカニズムの解明 (2020)
  • Author(s): 吉田一貴
  • Organizer: 第64回日本薬学会関東支部
• [Presentation] 骨髄由来マスト細胞のプリン受容体発現に対するIL-33の効果 (2020)
  • Author(s): 吉田一貴，石田悠，伊藤政明，松岡功
  • Organizer: 日本薬学会第140年会
• [Presentation] Effect of compound48/80 on antigen-dependent degranulation in BMMC (2020)
  • Author(s): Yoshida K，Takao T，Ito M，Matsuoka I
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Role of purinergic P2X4 receptors in antigen-induced mast cell degranulation and allergic responses (2020)
  • Author(s): Yoshida K
  • Organizer: 第49回日本免疫学会学術集会
• [Presentation] 粘膜型および組織型マスト細胞におけるP2X4 受容体を介する脱顆粒反応の調節 (2019)
  • Author(s): 吉田 一貴, 伊藤 政明, 古田 和幸, 田中 智之, 松岡 功
  • Organizer: 日本薬学会第139年会、千葉
• [Presentation] Role of ionotropic P2X receptor signalling in regulation of mast cell function (2018)
  • Author(s): Matsuoka I, Yoshida K, Hoshino Y, Ito M
  • Organizer: World Congress on Pharmacology and Toxicology, Rome
  • Int'l Joint Research
• [Presentation] Synergistic effect of ATP and prostaglandin E2 on mast cell degranulation (2018)
  • Author(s): Yoshida K, Ito M, Tajima M, Nagano T, Matsuoka I,
  • Organizer: The 18th WCP, Kyoto
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 偽アレルギー反応に伴う症状の予防若しくは抑制又は治療用の医薬組成物 (2022)
  • Inventor(s): 松岡功、伊藤政明、吉田一貴、今井利安
  • Industrial Property Rights Holder: 松岡功、伊藤政明、吉田一貴、今井利安
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-060261
  • Filing Date: 2022