Role of the active zone protein, ELKS, in insulin secretion from pancreatic beta cells

• Project/Area Number: 17K08547
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Kyorin University
• Principal Investigator: Ohara-Imaizumi Mica 杏林大学, 医学部, 教授 (40201941)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: インスリン分泌 / 膵β細胞 / アクティブゾーンタンパク質 / 極性分泌 / 刺激分泌連関 / 開口放出

Outline of Final Research Achievements

Pancreatic beta cells secrete insulin by Ca2+-triggered exocytosis. However, there is no apparent secretory site similar to the neuronal active zones, and the cellular and molecular localization mechanism underlying polarized exocytosis remains elusive. We demonstrated that active zone protein, ELKS and L-type voltage-dependent Ca2+ channels form a potent insulin secretion complex at the vascular side of the beta cell plasma membrane for polarized Ca2+ influx and insulin secretion from islets.

Academic Significance and Societal Importance of the Research Achievements

本研究によりアクティブゾーンタンパク質ELKSがインスリン分泌第１相において血管方向へのインスリン極性分泌をコントロールしていること、また2型糖尿病ではこの極性分泌機構がELKS発現低下により破綻している可能性を明らかにした。この結果は２型糖尿病のインスリン分泌不全の成因解明に貢献するだけでなく、従来の糖尿病薬とは異なる作用機序を持つELKSを標的とした新たな糖尿病治療薬の開発に繋がる可能性がある。

Research Products

• [Journal Article] Characterization of taste receptor-related G-protein α-gustducin in pancreatic β-cells. (2020)
  • Author(s): Udagawa H, Hiramoto M, Kawaguchi M, Uebanso T, Ohara-Imaizumi M, Nammo T, Nishimura W, Yasuda K.
  • Journal Title: J Diabetes Investig. Volume: In press. Issue: 4 Pages: 814-822
  • DOI: 10.1111/jdi.13214
  • NAID: 120006980550
  • Peer Reviewed / Open Access
• [Journal Article] Role of the active zone protein, ELKS, in insulin secretion from pancreatic β-cells (2019)
  • Author(s): Ohara-Imaizumi Mica、Aoyagi Kyota、Ohtsuka Toshihisa
  • Journal Title: Molecular Metabolism Volume: 27 Pages: 1213-1226
  • DOI: 10.1016/j.molmet.2019.06.017
  • Peer Reviewed / Open Access
• [Journal Article] TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets (2019)
  • Author(s): Araki Kunihiko、(他10名）、Ishigaki Shinsuke、Nakamichi Yoko、Tsunekawa Shin、Seino Yusuke、Yamamoto Akiko、Takayama Yasunori、Hidaka Shihomi、Tominaga Makoto、Ohara-Imaizumi Mica、Suzuki Atsushi、Ishiguro Hiroshi、Enomoto Atsushi、Yoshida Mari、Arima Hiroshi、Muramatsu Shin-ichi、Sobue Gen、Katsuno Masahisa
  • Journal Title: Journal of Clinical Investigation Volume: 129 Issue: 9 Pages: 3578-3593
  • DOI: 10.1172/jci124481
  • Peer Reviewed / Open Access
• [Journal Article] 膵β細胞のアクティブゾーンタンパク質ELKSが血管方向へのインスリン極性分泌をコントロールする (2019)
  • Author(s): 今泉美佳
  • Journal Title: Diabetes Journal Volume: 47 Pages: 168-170
• [Journal Article] アクティブゾーンタンパク質ELKSによるインスリン極性分泌調節機構 (2019)
  • Author(s): 今泉美佳
  • Journal Title: Diabetes Strategy Volume: 9 Pages: 156-157
• [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] VAMP7 Regulates Autophagosome Formation by Supporting Atg9a Functions in Pancreatic β-Cells From Male Mice (2018)
  • Author(s): Aoyagi Kyota、Itakura Makoto、Fukutomi Toshiyuki、Nishiwaki Chiyono、Nakamichi Yoko、Torii Seiji、Makiyama Tomohiko、Harada Akihiro、Ohara-Imaizumi Mica
  • Journal Title: Endocrinology Volume: 159 Issue: 11 Pages: 3674-3688
  • DOI: 10.1210/en.2018-00447
  • Peer Reviewed / Open Access
• [Journal Article] In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains. (2017)
  • Author(s): Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., Takahashi, S., Ando, K., Ohara-Imaizumi, M., Ishiguro, K., Hisanaga, S.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8602-8602
  • DOI: 10.1038/s41598-017-09239-5
  • Peer Reviewed / Open Access
• [Presentation] アクティブゾーンタンパク質のインスリン極性分泌における役割 (2019)
  • Author(s): 今泉美佳
  • Organizer: 第23回臨床内分泌病理学会
  • Invited
• [Presentation] 妊娠期膵β細胞でのP2X7受容体によるインスリン分泌亢進機構 (2019)
  • Author(s): 牧山智彦,青柳共太, 中道洋子,西脇知世乃,小泉修一,今泉美佳
  • Organizer: 第92回日本生化学会大会
• [Presentation] VAMP7 regulates autophagosome formation by supporting Atg9a functions in pancreatic beta-cells. (2019)
  • Author(s): 青柳共太,板倉誠,西脇知世乃,中道洋子,牧山智彦,今泉美佳
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] Role of active zone protein ELKS in insulin secretion from pancreatic β-cells (2019)
  • Author(s): Ohara-Imaizumi, M., Aoyagi, K. and Ohtsuka, T.
  • Organizer: 20th Anniversary Servier-IGIS Symposium
  • Int'l Joint Research / Invited
• [Presentation] アクティブゾーンタンパク質ELKSのインスリン分泌における役割 (2018)
  • Author(s): 今泉美佳、青柳共太、吉田昌史、飛田耶馬人、大倉正道、山内肇、﨑村建司、 中井淳一、加計正文、永松信哉、大塚稔久
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] Role of active zone protein ELKS in insulin exocytosis from pancreatic beta cells (2018)
  • Author(s): Ohara-Imaizumi, M
  • Organizer: Forefront of Neurotransmitter Release and Calcium Channel Signaling
  • Int'l Joint Research / Invited
• [Presentation] VAMP7 regulates autophagosome formation by supporting Atg9a functions in pancreatic β-cells (2018)
  • Author(s): 青柳共太、板倉誠、福冨俊之、西脇知世乃、中道洋子、鳥居征司、牧山智彦、原田彰宏、今泉美佳
  • Organizer: 第91回日本生化学会大会
• [Presentation] VAMP7 regulates autophagy to maintain mitochondrial homeostasis and to control insulin secretion in pancreatic β-cells. (2017)
  • Author(s): Aoyagi K., Itakura M., Nakamichi Y., Nishiwaki C., Torii S., Nagamatsu S.,& Ohara-Imaizumi M.
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] Role of active zone protein ELKS in insulin secretion from pancreatic β-cells. (2017)
  • Author(s): Ohara-Imaizumi M. Hida, Y., Yoshida, M., Aoyagi, K., Ohkura, M., Sakimura, K., Nakai, J., Kakei, M., Nagamatsu, S., Ohtsuka, T.
  • Organizer: 第11回Diabetes Leading-edge Conference
• [Presentation] 膵β細胞におけるVAMP7によるオートファゴソーム形成の制御機構 (2017)
  • Author(s): 青柳共太、西脇知世乃、中道洋子、福冨俊之、鳥居征司、牧山智彦、櫻井裕之、板倉誠、今泉美佳
  • Organizer: 第90回日本生化学会大会、第40回日本分子生物学会年会合同大会
• [Presentation] インスリン分泌におけるアクティブゾーンタンパク質の役割 (基調講演) (2017)
  • Author(s): 今泉美佳
  • Organizer: 第26回東京インスリン分泌研究会
  • Invited
• [Remarks] 杏林大学医学部 細胞生化学教室
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/insulin/
• [Remarks] 杏林大学医学部 生化学教室 細胞生物学グループ
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/insulin/
• [Remarks] 杏林大学医学部生化学教室
  • URL: http://www.kyorin-u.ac.jp/univ/user/medicine/insulin/