Elucidation of mechanisms and significance of Ca2+ channel-epigenetics coupling

• Project/Area Number: 16H05140
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: Mori Yasuo 京都大学, 工学研究科, 教授 (80212265)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: カルシウムチャネル / エピジェネティクス / ヒストン修飾 / 記憶 / 転写 / 副サブユニット / 長期記憶 / 転写調節 / てんかん / TRPチャネル / タンパク質複合体

Outline of Final Research Achievements

To understand the mechanism underlying long-term memories, I investigated the coupling of voltage-dependent Ca channels with epigenetic histone modification. In the nucleus, the Ca channel accessory subunit beta binds to the transcription factor TCF4 and suppresses transcription of genes via perturbation of TCA4-beta-catenin interaction. B56delta, the ezyme subunit of phosphatase 2A, interacts with the beta subunits to enhance cell proliferation by stimulating the G1 to S transition. The beta subunit is also critical for the formation of presynaptic complex comprising Ca channels, RIM, and synaptic vesicles.

Academic Significance and Societal Importance of the Research Achievements

脳神経系が活動した時にどのようにして脳神経系に蓄えられるかを明らかにするために行ってきた。この研究により、ヒトを含む動物にどのような刺激が加わると、どのように異なった変化が脳神経系に起こるかを、現象論だけでなく、明確な分子の定量的な変化によって示すことができる。また、ストレスは、過剰に加えられると脳神経系にダメージをもたらすが、適度なストレスはむしろ脳神経系の機能を亢進する。この線引きはどこにあるかといったような問いにも、重要なヒントを与えうる。

Research Products

• [Int'l Joint Research] Nantes大学(フランス)
• [Int'l Joint Research] ナント大学/INSERM/CNRS(フランス)
• [Int'l Joint Research] ナント大学/INSERM(フランス)
• [Int'l Joint Research] ブリティッシュコロンビア大学/トロント大学(カナダ)
• [Journal Article] ELKS/Voltage-dependent Ca2+ channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β-Cells. (2019)
  • Author(s): Ohara-Imaizumi, M., Aoyagi, K., Yamauchi, H., Yoshida, M., Mori, M.X., Hida, Y., Tran, H.N., Ohkura, M., Abe, M., Akimoto, Y., Nakamichi, Y., Nishiwaki, C., Kawakami, H., Hara, K., Sakimura, K., Nagamatsu, S., Mori, Y., Nakai, J., Kakei, M., and Ohtsuka, T.
  • Journal Title: Cell Reports Volume: 26 Issue: 5 Pages: 1213-1226
  • DOI: 10.1016/j.celrep.2018.12.106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPM2 confers susceptibility to social stress but is essential for behavioral flexibility. (2019)
  • Author(s): Andoh C, Nishitani N, Hashimoto E, Nagai Y, Takao K, Miyakawa T, Nakagawa T, Mori Y, Nagayasu K, Shirakawa H, Kaneko S.
  • Journal Title: Brain Res. Volume: 1704 Pages: 68-77
  • DOI: 10.1016/j.brainres.2018.09.031
  • NAID: 120006630995
  • Peer Reviewed
• [Journal Article] Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4. (2017)
  • Author(s): Rima M, Daghsni M, Lopez A, Fajloun Z, Lefrancois L, Dunach M, Mori Y, Merle P, Bruses JL, De Waard M, Ronjat M
  • Journal Title: Mol. Biol. Cell Volume: 28 Issue: 25 Pages: 3699-3708
  • DOI: 10.1091/mbc.e17-01-0076
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway. (2017)
  • Author(s): Liu X, Gong B, de Souza LB, Ong HL, Subedi KP, Cheng KT, Swaim W, Zheng C, Mori Y, Ambudkar IS.
  • Journal Title: Science Signal. Volume: 10 Issue: 482 Pages: 482-482
  • DOI: 10.1126/scisignal.aal4064
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The β4 subunit of the voltage-gated calcium channel (Cacnb4) regulates the rate of cell proliferation in Chinese Hamster Ovary cells. (2017)
  • Author(s): Rima M, Daghsni M, De Waard S, Gaborit N, Fajloun Z, Ronjat M, Mori Y, Bruses JL, De Waard M
  • Journal Title: Int. J. Biochem. Cell Biol. Volume: 89 Pages: 57-70
  • DOI: 10.1016/j.biocel.2017.05.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular and functional dissection of RIM protein multi-point interaction with P/Q-type Ca2+ channel CaV2.1 α1 subunits (2017)
  • Author(s): Hirano M, Takada Y, Wong CF, Yamaguchi K, Kotani K, Kurokawa T, Mori MX, Snutch TP, Ronjat M, De Waard M, Mori Y
  • Journal Title: J. Biol. Chem. Volume: 292 Issue: 22 Pages: 1-17
  • DOI: 10.1074/jbc.m117.778829
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Book] TRP Channels in the Brain: What Are They There For? (Chapter 17) in “Neurobiology of TRP channels” (2017)
  • Author(s): Sawamura S, Shirakawa H, Nakagawa T, Mori Y, Kaneko S
  • Total Pages: 10
  • Publisher: CRC Press/Taylor and Francis Group