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Clarification of molecular mechanism underlying Epac2A activation by antidiabetic sulfonylurea drugs

Research Project

Project/Area Number 24590320
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionKobe University

Principal Investigator

SHIBASAKI Tadao  神戸大学, 医学(系)研究科(研究院), 講師 (00323436)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordscAMP / Epac2A / スルホニル尿素薬 / インスリン分泌 / 膵β細胞 / 糖尿病 / ドッキングシミュレーション / FRET
Outline of Final Research Achievements

The incretin hormones potentiate insulin secretion by PKA-dependent and independent mechanisms, the latter involving Epac2A, which activates small G-protein Rap1. Epac2A is also a target of sulfonylureas (SU)s, widely used drugs in treatment of diabetes. In this study, the mechanism underlying the activation of Epac2A by SU was examined. Molecular docking simulation predicted the amino acid residues of Epac2A that interact with SUs. The predicted amino acids were mutated individually to alanine. Analyses of these mutants by FRET, SU binding, and Rap1 activity revealed that SU-binding site is located in the first cAMP-binding domain A and that binding of SUs to Epac2A depends on SU structures as well as the state of cAMP binding to Epac2A. Also, SU and cAMP synergistically activate Epac2A and its downstream signal Rap1. These data indicate that cAMP and SU cooperatively activate Epac2A through binding to cAMP-binding domain B and cAMP-binding domain A, respectively.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (44 results)

All 2015 2014 2013 2012 Other

All Journal Article (10 results) (of which Peer Reviewed: 6 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (33 results) (of which Invited: 4 results) Book (1 results)

  • [Journal Article] Role of Epac2A/Rap1 Signaling in Interplay Between Incretin and Sulfonylurea in Insulin Secretion.2015

    • Author(s)
      Takahashi H, Shibasaki T, Park JH, Hidaka S, Takahashi T, Ono A, Song DK, Seino S.
    • Journal Title

      Diabetes

      Volume: 64 Issue: 4 Pages: 1262-1272

    • DOI

      10.2337/db14-0576

    • NAID

      40020753234

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] インクレチンとスルホニル尿素薬の併用によるインスリン分泌増強におけるEpac2Aシグナルの役割2015

    • Author(s)
      柴崎忠雄、高橋晴美、清野 進
    • Journal Title

      最新医学 70巻増刊号 糖尿病と合併症(前篇)糖尿病

      Volume: 70 Pages: 473-497

    • Related Report
      2014 Annual Research Report
  • [Journal Article] cAMPとスルホニル尿素薬の相互作用によるEpac2Aの活性化とそのインスリン分泌における役割2015

    • Author(s)
      高橋晴美、高橋利匡、柴崎忠雄、清野 進
    • Journal Title

      Annual Review糖尿病・代謝・内分泌2015

      Volume: 1 Pages: 5-11

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion2014

    • Author(s)
      Gheni G, Ogura M, Iwasaki M, Yokoi N, Minami K, Nakayama Y, Harada K, Hastoy B, Wu X, Takahashi H, Kimura K, Matsubara T, Hoshikawa R, Hatano N, Sugawara K, Shibasaki T, Inagaki N, Bamba T, Mizoguchi A, Fukusaki E, Rorsman P, Seino S
    • Journal Title

      Cell Rep

      Volume: 9 Issue: 2 Pages: 661-673

    • DOI

      10.1016/j.celrep.2014.09.030

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cooperation between cAMP signaling and sulfonylurea in insulin secretion2014

    • Author(s)
      Shibasaki T, Takahashi T, Takahashi H, Seino S
    • Journal Title

      Diabetes Obes Metab

      Volume: 16 Suppl 1 Issue: S1 Pages: 118-125

    • DOI

      10.1111/dom.12343

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure.2013

    • Author(s)
      Kim M, Platt M, Shibasaki T, Quaggin S, Backx P, H, Seino S, Simpson J, Drucker DJ
    • Journal Title

      Nat Med

      Volume: 19 Issue: 5 Pages: 567-575

    • DOI

      10.1038/nm.3128

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Actin dynamics regulated by the balance of neuronal wiskott-aldrich syndrome protein (N-WASP) and cofilin activities detelmines the biphasic response of glucose-induced insulin secretion2013

    • Author(s)
      Uenishi E, Shibasaki T, Takahashi H, Seki C, Hamaguchi H, Yasuda T, Tatebe M, Oiso, Y, Takenawa T, Seino S.
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 288 Issue: 36 Pages: 25851-25864

    • DOI

      10.1074/jbc.m113.464420

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Antidiabetic Sulfonylureas and cAMP cooperatively activate Epac2A.2013

    • Author(s)
      Takahashi T, Shibasaki T, Takahashi H, Sugawara K, Ono A, Inoue N, Furuya T, Seino S
    • Journal Title

      Sci Signal

      Volume: 6 Issue: 298

    • DOI

      10.1126/scisignal.2004581

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] アクチンダイナミクスによるインスリン分泌の制御機構2013

    • Author(s)
      柴崎忠雄、清野 進
    • Journal Title

      Diabetes Frontier

      Volume: 24 Pages: 502-506

    • Related Report
      2013 Research-status Report
  • [Journal Article] 膵β細胞におけるcAMP情報伝達系、Epac2Aの役割2013

    • Author(s)
      柴崎忠雄、清野 進
    • Journal Title

      Islet Equality

      Volume: 2 Pages: 19-22

    • Related Report
      2013 Research-status Report
  • [Presentation] Interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion.2014

    • Author(s)
      Takahashi H, Shibasaki T, Park J-H, Hidaka S, Takahashi T, Ono A, Song D-K, Seino S
    • Organizer
      10th International Diabetes Federation Western Pacific Region Congress 2014 & 6th Scientific Meeting of the Asian Association for the Study of Diabetes
    • Place of Presentation
      Singapore
    • Year and Date
      2014-11-21 – 2014-11-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] インスリン分泌増強効果を有する新規低分子化合物の同定とその特性解析2014

    • Author(s)
      下野琴絵、菅原健二、柴崎忠雄、清野進
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-17
    • Related Report
      2014 Annual Research Report
  • [Presentation] 膵β細胞の3次元培養によるインクレチン/cAMP反応性の誘導2014

    • Author(s)
      柴崎忠雄、グプルジャンゲニ、マヒラアシム、岩崎真宏、星川律子、横井伯英、南幸太郎、清野進
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-16
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] インスリン分泌増強効果を有する新規低分子化合物の同定とその特性解析2014

    • Author(s)
      下野琴絵、菅原健二、柴崎忠雄、清野進
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] 膵β細胞におけるグルタミン酸動態の代謝フラックス解析2014

    • Author(s)
      吾甫尓江艾尼、横井伯英、星川律子、山口拓郎、岩崎真宏、小倉雅仁、南幸太郎、柴崎忠雄、清野進
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] スルホニル尿素(SU)薬とcAMPの協調作用によるEpac2A活性化2014

    • Author(s)
      柴崎忠雄、高橋利匡、高橋晴美、菅原健二、清野進
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-05-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] インクレチンとスルホニル尿素薬の併用によるインスリン分泌増強におけるEpac2A/Rap1シグナルの役割2014

    • Author(s)
      高橋晴美、柴崎忠雄、高橋利匡、日高志保美、小野愛夏、清野進
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-05-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] DPP-4阻害薬とSU薬の併用効果と重症低血糖:SU薬の種類による層別解析2014

    • Author(s)
      岡村香織、矢部大介、久保田章、黒瀬 健、高橋晴美、高橋利匡、柴崎忠雄、清野進、清野裕
    • Organizer
      第57回日本糖尿病学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-05-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Role of cAMP Sensor Epac2 in Insulin Secretion2013

    • Author(s)
      Shibasaki T
    • Organizer
      1st Korea-Japan Diabetes Forum (Symposium)
    • Place of Presentation
      Jeju, Korea
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] インスリン分泌:Up to Date、インスリン分泌におけるcAMPセンサーEpac2の役割2013

    • Author(s)
      柴崎忠雄
    • Organizer
      第50回日本糖尿病学会近畿地方会(教育講演)
    • Place of Presentation
      京都
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Interaction of incretin and sulfonylurea through Epac2A signaling in insulin secretion2013

    • Author(s)
      Takahashi H, Shibasaki T, Hidaka S, Ono A, Takahashi T, Seino S
    • Organizer
      第56回日本糖尿病学会年次学術集会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] The role of malate-aspartate shuttle-derived glutamate in incretin-potentiated insulin secretion2013

    • Author(s)
      Ogura M, Iwasaki M, Ghupurjan G, Minami K, Yokoi N, Shibasaki T, Seino S
    • Organizer
      第56回日本糖尿病学会年次学術集会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] Identification and characterization of the binding site and properties of antidiabetic sulfonylurea drugs in the cAMP sensor Epac2A2013

    • Author(s)
      Takahashi T, Shibasaki T, Takahashi H, Sugawara K, Ono A, Seino S
    • Organizer
      Beta Cell Workshop 2013 Kyoto
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Research-status Report
  • [Presentation] Interaction of incretin and sulfonylurea through Epac2 in insulin secretion2013

    • Author(s)
      Takahashi H, Shibasaki T, Hidaka S, Takahashi T, Ono A, Seino S
    • Organizer
      Beta Cell Workshop 2013 Kyoto
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Research-status Report
  • [Presentation] Induction of cAMP responsiveness by formation of pseudoislets2013

    • Author(s)
      Gheni G, Iwasaki M, Ogura M, Yokoi N, Shibasaki T, Minami K, Seino S
    • Organizer
      Beta Cell Workshop 2013 Kyoto
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Research-status Report
  • [Presentation] Epac2/Rap1を介したインスリン分泌における下流シグナルの探索2013

    • Author(s)
      柴崎忠雄、堰千紘、髙橋晴美、清野 進
    • Organizer
      第56回日本糖尿病学会年次学術集会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] Critical Role of Actin Dynamics Regulated by N-WASP and Cofilin in the Biphasic Response of Glucose-Induced Insulin Secretion2013

    • Author(s)
      Shibasaki T, Uenishi E, Takahashi H, Oiso Y, Seino S
    • Organizer
      American Diabetes Association's 73rd Scientific Sessions
    • Place of Presentation
      Chicago, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] Sulfonylureas act as an enhancer of Epac2 activation in cAMP-induced insulin secretion2013

    • Author(s)
      Takahashi T, Shibasaki T, Takahashi H, Sugawara K, Ono A, Seino S
    • Organizer
      American Diabetes Association's 73rd Scientific Sessions
    • Place of Presentation
      Chicago, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] The role of Malate-aspartate shuttle derived glutamate in incretin potentiated insulin secretion2013

    • Author(s)
      Gheni G, Iwasaki M, Ogura M, Minami K, Yokoi N, Shibasaki T, Takahashi H, Sugawara K, Seino S
    • Organizer
      5th International Uyghur Academy Conference
    • Place of Presentation
      Istanbul, Turkey
    • Related Report
      2013 Research-status Report
  • [Presentation] Interaction of incretin and sulfonylurea through Epac2A signaling in insulin secretion2013

    • Author(s)
      Takahashi H, Shibasaki T, Hidaka S, Ono A, Takahashi T, Seino S
    • Organizer
      49th Annual Meeting of the European Association for the Study of Diabetes
    • Place of Presentation
      Spain, Barcelona
    • Related Report
      2013 Research-status Report
  • [Presentation] Interaction of incretin and sulfonylurea through Epac2A in insulin secretion2013

    • Author(s)
      Takahashi H, Shibasaki T, Hidaka S, Takahashi T, Ono A, Seino S
    • Organizer
      2013 International Conference on Diabetes and Metabolism & 5th Scientific Meeting of the Asian Association for the Study of Diabetes
    • Place of Presentation
      Seoul, Korea
    • Related Report
      2013 Research-status Report
  • [Presentation] Clarification of molecular mechanism underlying Epac2A activation by antidiabetic sulfonylurea drugs2013

    • Author(s)
      Shibasaki T, Takahashi T, Takahashi H, Sugawara K, Seino S
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸
    • Related Report
      2013 Research-status Report
  • [Presentation] Interaction of incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion2013

    • Author(s)
      Takahashi H, Shibasaki T, Hidaka S, Ono A, Takahashi T, Seino S
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸
    • Related Report
      2013 Research-status Report
  • [Presentation] 膵臓β細胞内インスリン顆粒動態シミュレーションモデルに関する研究2013

    • Author(s)
      田畑直紀、松本卓也 、玉置 久 、柴崎忠雄、清野 進、福島光夫、須永泰弘、横田秀夫
    • Organizer
      ISLiMソフトウェア研究開発報告会
    • Place of Presentation
      東京
    • Related Report
      2012 Research-status Report
  • [Presentation] インスリン分泌におけるcAMPセンサーEpac2Aの機能とその役割の解明

    • Author(s)
      柴崎忠雄
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] SU薬によるEpac2A活性化機構の解明

    • Author(s)
      高橋利匡、髙橋晴美、小野愛夏、柴崎忠雄、清野 進
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] 膵β細胞におけるインクレチン/cAMPシグナルとグルコース代謝の相互作用

    • Author(s)
      小倉雅仁、岩崎真宏、吾甫尓江艾尼、南幸太郎、柴崎忠雄、中山泰宗、原田和生、馬場健史、福崎英一郎、清野 進
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] 膵β細胞間相互作用によるインクレチン/cAMPシグナル応答性の誘導

    • Author(s)
      吾甫尓江艾尼、岩崎真宏、小倉雅仁、柴崎忠雄、南幸太郎、清野 進
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] 膵β細胞のN-WASPとcofilinによるF-アクチンリモデリングの制御とそのインスリン分泌における役割

    • Author(s)
      上西栄太、柴崎忠雄、高橋晴美、濱口ひとみ、大磯ユタカ、清野 進
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] インクレチンとSU薬によるインスリン顆粒開口分泌

    • Author(s)
      高橋晴美、柴崎忠雄、高橋利匡、清野 進
    • Organizer
      第55回日本糖尿病学会年次学術集会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] Regulation of actin dynamics by N-WASP and cofilin in pancreatic beta-cells and its role in insulin secretion

    • Author(s)
      Shibasaki T, Uenishi E, Takahashi H, Hamaguchi H, Oiso Y, Seino S
    • Organizer
      9th International Diabetes Federation Western Pacific Region Congress/4th Scientific Meeting of the Asian Association for the Study of Diabetes
    • Place of Presentation
      Kyoto
    • Related Report
      2012 Research-status Report
  • [Presentation] Role of actin dynamics regulated by N-WASP and cofilin in insulin secretion in pancreatic beta-cells

    • Author(s)
      Shibasaki T, Uenishi E, Takahashi H, Hamaguchi H, Seino S
    • Organizer
      第35 回日本分子生物学会年会
    • Place of Presentation
      福岡
    • Related Report
      2012 Research-status Report
  • [Presentation] 膵臓β細胞内インスリン顆粒動態シミュレーションモデルに関する研究

    • Author(s)
      田畑直紀、松本卓也 、玉置 久 、柴崎忠雄、清野 進、福島光夫、須永泰弘、横田秀夫
    • Organizer
      「グランドチャレンジ・アプリケーションの研究開発」公開シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2012 Research-status Report
  • [Book] Annual Review糖尿病・代謝・内分泌20122012

    • Author(s)
      高橋晴美、柴崎忠雄、清野 進
    • Publisher
      糖尿病 基礎分野での進歩 膵β細胞におけるEpac2Aの役割
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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