Functional role of intracellular muscarinic receptor for hippocampal adult neurogenesis

• Project/Area Number: 16K19012
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Uwada Junsuke 旭川医科大学, 医学部, 助教 (70580314)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ムスカリン受容体 / 神経新生 / MAPキナーゼ / 薬理学 / 脳・神経 / 受容体

Outline of Final Research Achievements

Neurogenesis in the hippocampal dentate gyrus is important to generate and maintain functional neurons, therefore which has gained interest as clinical target of neurological diseases, like dementia. In this study, we found the neural stem cells in hippocampal dentate gyrus express functional intracellular muscarinic M1 receptor. Stimulation of intracellular M1 receptors activated MAP kinase (ERK1/2) signaling. Our results indicate that muscarinic stimulation might contribute to the proliferation and maintenance of neural stem cells in hippocampal dentate gyrus through activation of intracellular M1 receptors.

Academic Significance and Societal Importance of the Research Achievements

海馬歯状回は成人においても神経細胞が新しく作られる神経新生の場であり、認知症など加齢に伴う神経疾患に関わるものとして着目されている。一方、アセチルコリンの受容体であるムスカリンM1受容体はこれまで細胞の表面に存在して働くと考えられてきた。本研究で我々は細胞の内部に局在するM1受容体が細胞の増殖や維持に関わるシグナルを引き起こすことを明らかにし、神経新生を亢進する新たな治療ターゲットとなりうる可能性を示した。

Research Products

• [Journal Article] Augmentation of endogenous acetylcholine uptake and cholinergic facilitation of hippocampal long-term potentiation by acetylcholinesterase inhibition (2019)
  • Author(s): Masuoka T, Uwada J, Kudo M, Yoshiki H, Yamashita Y, Taniguchi T, Nishio M, Ishibashi T, Muramatsu I
  • Journal Title: Neuroscience Volume: 404 Pages: 39-47
  • DOI: 10.1016/j.neuroscience.2019.01.042
  • Peer Reviewed / Open Access
• [Journal Article] Novel regulatory systems for acetylcholine release in rat striatum and anti‐Alzheimer's disease drugs (2019)
  • Author(s): Muramatsu Ikunobu、Uwada Junsuke、Yoshiki Hatsumi、Sada Kiyonao、Lee Kung‐Shing、Yazawa Takashi、Taniguchi Takanobu、Nishio Matomo、Ishibashi Takaharu、Masuoka Takayoshi
  • Journal Title: Journal of Neurochemistry Volume: 印刷中 Issue: 5 Pages: 605-623
  • DOI: 10.1111/jnc.14701
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. (2019)
  • Author(s): Mikami D, Kobayashi M, Uwada J, Yazawa T, Kamiyama K, Nishimori K, Nishikawa Y, Morikawa Y, Yokoi S, Takahashi N, Kasuno K, Taniguchi T, Iwano M.
  • Journal Title: Life Sci Volume: 222 Pages: 125-132
  • DOI: 10.1016/j.lfs.2019.03.008
  • Peer Reviewed / Open Access
• [Journal Article] A New Aspect of Cholinergic Transmission in the Central Nervous System (2018)
  • Author(s): Muramatsu Ikunobu、Masuoka Takayoshi、Uwada Junsuke、Yoshiki Hatsumi、Yazama Takashi、Lee Kung-Shing、Sada Kiyonao、Nishio Matomo、Ishibashi Takaharu、Taniguchi Takanobu
  • Journal Title: Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Volume: 1 Pages: 45-58
  • DOI: 10.1007/978-981-10-8488-1_3
  • ISBN: 9789811084874, 9789811084881
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A short-chain fatty acid, propionate, enhances the cytotoxic effect of cisplatin by modulating GPR41 signaling pathways in HepG2 cells (2018)
  • Author(s): Kobayashi M, Mikami D, Uwada J, Yazawa T, Kamiyama K, Kimura H, Taniguchi T, Iwano M
  • Journal Title: Oncotarget Volume: 9 Issue: 59 Pages: 31342-31354
  • DOI: 10.18632/oncotarget.25809
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role of Cysteine String Protein Alpha (CSPα) Phosphorylation at Serine 10, and 34, by Protein Kinase Cγ for Presynaptic Maintenance. (2018)
  • Author(s): Shirafuji T, Ueyama T, Adachi N, Yoshino KI, Sotomaru Y, Uwada J, Kaneoka A, Ueda T, Tanaka S, Hide I, Saito N, Sakai N
  • Journal Title: J. Neurosci. Volume: 38 Issue: 2 Pages: 278-290
  • DOI: 10.1523/jneurosci.1649-17.2017
  • Peer Reviewed
• [Journal Article] Activation of muscarinic receptors prevents TNF-α-mediated intestinal epithelial barrier disruption through p38 MAPK (2017)
  • Author(s): Uwada Junsuke、Yazawa Takashi、Islam Md Tariqul、Khan Md Rafiqul Islam、Krug Susanne M.、Fromm Michael、Karaki Shin-ichiro、Suzuki Yuichi、Kuwahara Atsukazu、Yoshiki Hatsumi、Sada Kiyonao、Muramatsu Ikunobu、Taniguchi Takanobu
  • Journal Title: Cellular Signalling Volume: 35 Pages: 188-196
  • DOI: 10.1016/j.cellsig.2017.04.007
  • NAID: 120006491645
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of synaptic acetylcholine concentrations by acetylcholine transport in rat striatal cholinergic transmission (2017)
  • Author(s): Muramatsu Ikunobu、Uwada Junsuke、Masuoka Takayoshi、Yoshiki Hatsumi、Sada Kiyonao、Lee Kung-Shing、Nishio Matomo、Ishibashi Takaharu、Taniguchi Takanobu
  • Journal Title: Journal of Neurochemistry Volume: 143 Issue: 1 Pages: 76-86
  • DOI: 10.1111/jnc.14127
  • Peer Reviewed
• [Journal Article] Diethylstilbestrol administration inhibits theca cell androgen and granulosa cell estrogen production in immature rat ovary (2017)
  • Author(s): Imamichi, Y., Sekiguchi, T., Kitano, T., Kajitani, T., Okada, R., Inaoka, Y., Miyamoto, K., Uwada, J., Takahashi, S., Nemoto, T., Mano, A., Khan, M.R.I., Islam, M.T., Yuhki, K., Kashiwagi, H., Ushikubi, F., Suzuki, N., Taniguchi, T., Yazawa, T.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8374-8374
  • DOI: 10.1038/s41598-017-08780-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological evidence of specific acetylcholine transport in rat cerebral cortex and other brain regions. (2016)
  • Author(s): Ikunobu Muramatsu, Hatsumi Yoshiki, Junsuke Uwada, Takayoshi Masuoka, Kiyonao Sada, Takanobu Taniguchi, Matomo Nishio.
  • Journal Title: Journal of Neurochemistry Volume: 139 Issue: 4 Pages: 566-575
  • DOI: 10.1111/jnc.13843
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review] (2016)
  • Author(s): 1.Yazawa, T., Imamichi, Y., Miyamoto, M., Khan, MR., Uwada, J., Umezawa, A., Taniguchi, T.:
  • Journal Title: Endocrine Journal Volume: 63 Issue: 11 Pages: 943-951
  • DOI: 10.1507/endocrj.EJ16-0373
  • NAID: 130005170487
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ムスカリン受容体のストア作動性カルシウム流入を介したp38 MAPキナーゼ制御 (2018)
  • Author(s): 宇和田 淳介、矢澤 隆志、谷口 隆信
  • Organizer: 第91回日本生化学会大会
• [Presentation] Molecular mechanism of muscarinic receptor-mediated suppression of TNF-α-induced intestinal epithelial barrier disruption. (2017)
  • Author(s): 宇和田淳介、矢澤隆志、Md Tariqul Islam、谷口隆信
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] Molecular mechanism of muscarinic receptor-mediated suppression of TNF-α-induced inflammation through p38 MAP kinase. (2017)
  • Author(s): 宇和田淳介、矢澤隆志、Md Tariqul Islam、谷口隆信
  • Organizer: 第90回日本生化学会大会
• [Presentation] ムスカリン受容体刺激はTNF受容体の切断を促進することで腸上皮細胞におけるTNF-αシグナリングを抑制する (2016)
  • Author(s): 宇和田淳介、Md Rafiqul Islam Khan、矢澤隆志、Md Tariqul Islam、谷口隆信
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] 腸上皮細胞におけるムスカリン受容体を介したTNF-αシグナリングの制御 (2016)
  • Author(s): 宇和田淳介、Md Rafiqul Islam Khan、矢澤隆志、Md Tariqul Islam、谷口隆信
  • Organizer: 第67回日本薬理学会北部会
  • Place of Presentation: 札幌
• [Presentation] TNF-αによって誘導される腸上皮バリア機能低下に対するムスカリン受容体の役割 (2016)
  • Author(s): 宇和田淳介、Md Rafiqul Islam Khan、矢澤隆志、Md Tariqul Islam、谷口隆信
  • Organizer: 第114回北海道癌談話会例会
  • Place of Presentation: 札幌
• [Book] Binding method for detection of muscarinic acetylcholine receptors in receptor’s natural environment (Neuromethods, Volume 107) (2016)
  • Author(s): Muramatsu I, Yoshiki H, Sada K, Uwada J, Taniguchi T, Masuoka T, Nishio M
  • Total Pages: 13
  • Publisher: Humana Press