Study of the regulatory mechanism of ETAR and ETBR level by receptor binding protein and the relevance between clinical significance and endothelin receptor level.

• Project/Area Number: 21390068
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Hokkaido University
• Principal Investigator: MIWA Soichi 北海道大学, 大学院・医学研究科, 教授 (40157706)
• Co-Investigator(Kenkyū-buntansha): NISHIYA Tadashi 北海道大学, 大学院・医学研究科, 講師 (80399831) ; HORINOUCHI Takahiro 北海道大学, 大学院・医学研究科, 講師 (20307771) ; TERADA Koji 北海道大学, 大学院・医学研究科, 助教 (70342722) ; NISHIMOTO Arata 北海道大学, 大学院・医学研究科, 助教 (90396325)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2009: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: エンドセリン受容体 / ユビキチン化 / 受容体結合タンパク質 / タンパク質分解 / trafficking / エンドセリン / Jab1 / ユビキチン / 酵母ツーハイブリッド法 / 細胞内移行 / 蛋白質分解 / リン酸化

Research Abstract

We identified Jab1 as a C-tail binding protein of endothelin receptors (ETRs), including ET_AR and ET_BR and showed that Jab1 regulates receptor levels via ubiquitination of ETRs. We also found that ubiquitination level of ET_BR was increased upon endothelin-1 (ET-1) stimulation. Moreover, we indicated that the ubiquitination was required for ET-1-induced ET_BR internalization. Thus, we have demonstrated that ubiquitination has an important role in the regulation of trafficking of ETRs.

Research Products

• [Journal Article] Adenylate cyclase-cAMP-protein kinase A signaling pathway inhibits endothelin type A receptor-operated Ca2+ entry mediated via TRPC6 channels (2012)
  • Author(s): Horinouchi T., Higa T., Aoyagi H., Nishiya T., Terada K. and Miwa S.
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: 340 Pages: 143-151
  • Peer Reviewed
• [Journal Article] Function and regulation of endothelin type A receptor-operated TRPC channels (2012)
  • Author(s): Horinouchi T., Terada K., Higa T., Aoyagi H., Nishiya T., Suzuki H. and Miwa S.
  • Journal Title: J. Pharmacol. Sci. Volume: 340 Pages: 143-151
  • Peer Reviewed
• [Journal Article] Nicotine-and tar-free cigarette smoke induces cell damage through reactive oxygen species newly generated by PKC-dependent activation of NADPH oxidase (2012)
  • Author(s): Asano H., Horinouchi T., Mai Y., Sawada O., Fujii S., Nishiya T., Minami M., Katayama T., Iwanaga T., Terada K. and Miwa S.
  • Journal Title: J. Pharmacol. Sci. Volume: 118 Pages: 275-287
  • NAID: 10030455160
  • Peer Reviewed
• [Journal Article] Nicotine- and tar-free cigarette smoke induces cell damage through reactive oxygen species newly generated by PKC-dependent activation of NADPH oxidase (2012)
  • Author(s): Asano H, et al
  • Journal Title: J.Pharmacol.Sci Volume: 118 Pages: 275-287
  • Peer Reviewed
• [Journal Article] Adenylate cyclase-cAMP-protein kinase A signaling pathway inhibits endothelin type A receptor-operated Ca^<2+> entry mediated via TRPC6 channels (2012)
  • Author(s): Horinouchi T, et al
  • Journal Title: J.Pharmacol.Exp.Ther Volume: 340 Pages: 143-151
  • Peer Reviewed
• [Journal Article] The ECS(SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase (2011)
  • Author(s): Matsumoto K., Nishiya T., Maekawa S., Horinouchi T., Ogasawara K., Uehara T and Miwa S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 409 Pages: 46-51
  • Peer Reviewed
• [Journal Article] Effect of cigarette smoke components on vascular smooth muscle cell migration toward platelet-derived growth factor BB. (2011)
  • Author(s): Yoshiyama S., Horinouchi T., Miwa S., Wang H. H., Kohama K. and Nakamura A.
  • Journal Title: J. Pharmacol. Sci. Volume: 115 Pages: 532-535
  • NAID: 10029893589
  • Peer Reviewed
• [Journal Article] Regulation of inducible nitric-oxide synthase by the SPRY domain-and SOCS box-containing proteins (2011)
  • Author(s): Nishiya T., Matsumoto K., Maekawa S., Kajita E., Horinouchi T., Fujimuro M., Ogasawara K., Uehara T. and Miwa S.
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 9009-9019
  • Peer Reviewed
• [Journal Article] Juvenile stress attenuates the dorsal hippocampal postsynaptic 5-HT1A receptor function in adult rats (2011)
  • Author(s): Matsuzaki H., Izumi T., Horinouchi T., Boku S., Inoue T., Yamaguchi T., Yoshida T., Matsumoto M., Togashi H., Miwa S., Koyama T. and Yoshioka M.
  • Journal Title: Psychopharmacology (Berl) Volume: 214 Pages: 329-337
  • Peer Reviewed
• [Journal Article] Function and regulation of endothelin type A receptor-operated transient receptor potential canonical channels (2011)
  • Author(s): Horinouchi T, et al
  • Journal Title: J.Pharmacol.Sci Volume: 117 Pages: 295-306
  • NAID: 10030453850
  • Peer Reviewed
• [Journal Article] The ECS(SPSB)E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase (2011)
  • Author(s): Matsumoto K, et al
  • Journal Title: Biochem.Biophys.Res.Commun Volume: 409 Pages: 46-51
  • Peer Reviewed
• [Journal Article] Regulation of inducible nitric oxide synthase by the SPRY domain- and SOCS box-containing proteins (2011)
  • Author(s): Nishiya T, et al
  • Journal Title: J.Biol.Chem Volume: 286 Pages: 9009-9019
  • Peer Reviewed
• [Journal Article] Effect of cigarette smoke components on vascular smooth muscle cell migration toward platelet-derived growth factor BB (2011)
  • Author(s): Yoshiyama S, et al
  • Journal Title: J.Pharmacol.Sci Volume: 115 Pages: 532-535
  • Peer Reviewed
• [Journal Article] Juvenile stress attenuates the dorsal hippocampal postsynaptic 5-HT(1A) receptor function in adult rats. (2011)
  • Author(s): Matsuzaki H, et al.
  • Journal Title: Psychopharmacology(Berl). Volume: 214 Pages: 329-337
  • Peer Reviewed
• [Journal Article] Regulation of inducible nitric oxide synthase by the SPRY domain- and SOCS box-containing proteins. (2011)
  • Author(s): Nishiya T, et al.
  • Journal Title: J Biol Chem. Volume: 286 Pages: 9009-9019
  • Peer Reviewed
• [Journal Article] Effect of Cigarette Smoke Components on Vascular Smooth Muscle Cell Migration Toward Platelet-Derived Growth Factor BB. (2011)
  • Author(s): Yoshiyama S, et al.
  • Journal Title: J Pharmacol Sci. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Endothelin type Breceptor-induced sustained Ca2+ influx involves G(q/11)/phospholipase C-independent, p38 mitogen-activated protein kinase-dependent activation of Na+/H+ exchanger. (2010)
  • Author(s): Higa T., Horinouchi T., Aoyagi H., Asano H., Nishiya T., Nishimoto A., Muramatsu I. and Miwa S.
  • Journal Title: J. Pharmacol. Sci. Volume: 113 Pages: 276-280
  • Peer Reviewed
• [Journal Article] Jab1 regulates levels of endothelin type A and B receptors by promoting ubiquitination and degradation. (2010)
  • Author(s): Nishimoto A., Lu L., Hayashi M., Nishiya T., Horinouchi T. and Miwa S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 391 Pages: 1616-1622
  • NAID: 120001909636
  • Peer Reviewed
• [Journal Article] Endothelin type B receptor-induced sustained Ca2+ influx involves G(q/11)/phospholipase C-independent, p38 mitogen-activated protein kinase-denendent activation of Na+/H+ exchanger. (2010)
  • Author(s): Higa T, et al.
  • Journal Title: J Pharmacol Sci. Volume: 113 Pages: 276-280
  • Peer Reviewed
• [Journal Article] Jab1 regulates levels of endothelin type A and B receptors by promoting ubiquitination and degradation. (2010)
  • Author(s): Nishimoto A, et al
  • Journal Title: Biochem Biophys Res Commun 391(4) Pages: 1616-22
  • NAID: 120001909636
  • Peer Reviewed
• [Journal Article] Differential coupling of human endothelin type A receptor to G(q/11) and G(12) proteins : the functional significance of receptor expression level in generating multiple receptor signaling. (2009)
  • Author(s): Horinouchi T., Asano H., Higa T., Nishimoto A., Nishiya T., Muramatsu I. and Miwa S.
  • Journal Title: J. Pharmacol. Sci. Volume: 111 Pages: 338-351
  • NAID: 130000132483
  • Peer Reviewed
• [Journal Article] Pharmacological evaluation of ocular beta-adrenoceptors in rabbit by tissue segment binding method. (2009)
  • Author(s): Hrinouchi T., Morishima S., Tanaka Y., Koike K., Miwa S. and Muramatsu I.
  • Journal Title: Life Sci. Volume: 84 Pages: 181-187
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of sustained Ca2+ influx triggerd by G protein-coupled receptors (2009)
  • Author(s): Horinouchi T, Miwa S
  • Journal Title: Nippon Yakurigaku Zasshi. 134(1) Pages: 8-12
  • NAID: 10025741036
  • Peer Reviewed
• [Journal Article] Differential coupling of human endothelin type A receptor to G(q/11)and G(12)proteins : the functional significance of receptor expression level in generating multiple receptor signaling. (2009)
  • Author(s): Horinouchi T, et al
  • Journal Title: J Pharmacol Sciences. 111(4) Pages: 338-51
  • NAID: 130000132483
  • Peer Reviewed
• [Presentation] PKAリン酸化によるエンドセリンA型受容体作動性TRPC6チャネルの抑制性制御機構 (2012)
  • Author(s): 堀之内孝広
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2012-03-15
• [Presentation] エンドセリンA型受容体刺激によって誘発されるTRPC3及びTRPC6チャネルを介した受容体作動性Ca^<2+>流入の制御機構 (2012)
  • Author(s): 比嘉綱己
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2012-03-15
• [Presentation] エンドセリン受容体の動態制御におけるユビキチン修飾の役割 (2012)
  • Author(s): 寺田晃士
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2012-03-15
• [Presentation] ニコチン・タール除去タバコ煙水抽出液によるNADPHオキシダーゼ依存性細胞傷害の分子メカニズム (2012)
  • Author(s): 眞井洋輔
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2012-03-15
• [Presentation] プロテインキナーゼAによるTRPC6チャネルを介したエンドセリンA型受容体作動性Ca^<2+>流入の抑制性制御の分子機構 (2011)
  • Author(s): 比嘉綱己
  • Organizer: 第21回日本循環薬理学会
  • Place of Presentation: 岡山大学創立五十周年記念館(岡山市)
  • Year and Date: 2011-12-02
• [Presentation] エンドセリンA型受容体作動性TRPC6チャネルの抑制性機能制御に関与するPKAリン酸化部位の同定 (2011)
  • Author(s): 堀之内孝広
  • Organizer: 第39回薬物活性シンポジウム
  • Place of Presentation: 福岡大学福大メディカルホール(福岡市)
  • Year and Date: 2011-11-21
• [Presentation] Phos-tag^<TM>biotinを用いたエンドセリンA型受容体作動性TRPC6チャネルのPKAによるリン酸化部位の同定 (2011)
  • Author(s): 堀之内孝広
  • Organizer: 第62回日本薬理学会北部会
  • Place of Presentation: 江陽グランドホテル(宮城県)
  • Year and Date: 2011-09-29
• [Presentation] Phos-tag^<TM> biotinを用いたエンドセリンA型受容体作動性TRPC6チャネルのPKAによるリン酸化部位の同定 (2011)
  • Author(s): 堀之内孝広
  • Organizer: 第62回日本薬理学会北部会
  • Place of Presentation: 江陽グランドホテル(宮城県)
  • Year and Date: 2011-09-29
• [Presentation] 誘導型NO合成酵素のユビキチン・プロテアソーム依存的分解制御機構 (2011)
  • Author(s): 松本一馬
  • Organizer: 第25回北海道薬物作用談話会
  • Place of Presentation: 酪農学園大学中央館学生ホール(北海道)
  • Year and Date: 2011-07-23
• [Presentation] 誘導型NO合成酵素のユビキチン・プロテアソーム依存的分解制御機構 (2011)
  • Author(s): 松本一馬
  • Organizer: 第25回北海道薬物作用談話会
  • Place of Presentation: 酪農学園大学中央館学生ホール(札幌市)
  • Year and Date: 2011-07-23
• [Presentation] アデニル酸シクラーゼ/cAMP/PKA系によるエンドセリンA型受容体作動性TRPC6チャネルの負の制御機構 (2011)
  • Author(s): 堀之内孝広
  • Organizer: 第84回日本薬理学会年会
  • Year and Date: 2011-03-24
• [Presentation] PRY domainとSOCS boxタンパク質による誘導型-酸化窒素合成酵素の分解制御機構 (2011)
  • Author(s): 西屋禎
  • Organizer: 第84回日本薬理学会年会
  • Year and Date: 2011-03-23
• [Presentation] SPRY domainとSOCS boxタンパク質による誘導型一酸化窒素合成酵素の分解制御機構 (2011)
  • Author(s): 西屋禎
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 震災のため,誌上開催
  • Year and Date: 2011-03-23
• [Presentation] エンドセリンA型受容体作動性TRPC6チャネルの多様な機能制御機構 (2011)
  • Author(s): 堀之内孝広
  • Organizer: 第40回日本心脈管作動物質学会
  • Place of Presentation: かがわ国際会議場・サンポートホール高松(香川県)
  • Year and Date: 2011-02-04
• [Presentation] cAMP/PKA系によるエンドセリンA型受容体作動性TRPC6チャネルの抑制性機能制御 (2010)
  • Author(s): 堀之内孝広
  • Organizer: 第61回日本薬理学会北部会
  • Place of Presentation: 札幌コンベンションセンター(北海道)
  • Year and Date: 2010-09-10
• [Presentation] Molecular mechanism of E T_AR-operated Ca^<2+> entry via TRPC channels and visualization of homo-and heteromeric TRPC3/6 interaction in living cells using BiFC. (2010)
  • Author(s): 堀之内孝広
  • Organizer: 16^<th> World Congress of Basic and Clinical Pharmacology
  • Place of Presentation: Bella Center(デンマーク)
  • Year and Date: 2010-07-19
• [Presentation] Molecular mechanism of ET_AR-operated Ca^<2+> entry via TRPC channels and visualization of homo- and heteromeric TRPC3/6 interaction in living cells using BiFC. (2010)
  • Author(s): 堀之内孝広
  • Organizer: 16^<th> World Congress of Basic and Clinical Pharmacology.
  • Place of Presentation: Bella Center(デンマーク)
  • Year and Date: 2010-07-19
• [Presentation] Visualization of homo-and heteromeric TRPC3/6 interaction in living cells using bimolecular fluorescence complementation analysis (2010)
  • Author(s): Horinouchi T.
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] Molecular mechanisms for endothelin type A receptor-operated Ca^<2+> entry via TRPC3 and TRPC6 (2010)
  • Author(s): Horinouchi T.
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] Regulation of endothelin receptor levels by receptor binding protein, Jab1 (2010)
  • Author(s): Nishimoto A.
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] Visualization of homo- and heteromeric TRPC3/6 interaction in living cells using bimolecular fluorescence complementation analysis (2010)
  • Author(s): Horinouchi T
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] 受容体結合蛋白質Jab1によるエンドセリン受容体の発現レベル調節機構 (2009)
  • Author(s): 西本新
  • Organizer: 第19回日本循環薬理学会
  • Place of Presentation: 京都大学百周年時計台記念館(京都府)
  • Year and Date: 2009-11-27
• [Presentation] エンドセリンA受容体作動性Ca2+流入に関与するTRPCチャネルの活性化機構 (2009)
  • Author(s): 堀之内孝広
  • Organizer: 第19回日本循環薬理学会
  • Place of Presentation: 京都大学百周年時計台記念館(京都府)
  • Year and Date: 2009-11-27
• [Presentation] エンドセリンÅ受容体作動性Ca^<2+>流入に関与するTRPCチャネルの活性化機構 (2009)
  • Author(s): 堀之内孝広
  • Organizer: 第19回日本循環薬理学会
  • Place of Presentation: 京都大学百周年時計台記念館(京都府)
  • Year and Date: 2009-11-27
• [Presentation] 蛍光タンパク質構成法を用いたエンドセリンA型受容体作動性TRPCチャネルの分子間相互作用の可視化 (2009)
  • Author(s): 堀之内孝広
  • Organizer: 第60回日本薬理学会北部会
  • Place of Presentation: 富山国際会議場(富山県)
  • Year and Date: 2009-09-26
• [Presentation] 受容体結合蛋白質Jab1によるエンドセリン受容体の発現レベル調節機構 (2009)
  • Author(s): 西本新
  • Organizer: 第60回日本薬理学会北部会
  • Place of Presentation: 富山国際会議場(富山県)
  • Year and Date: 2009-09-26
• [Presentation] エンドセリンA型受容体作動性Ca2+流入に関与するTRPCチャネルの同定 (2009)
  • Author(s): 比嘉綱己
  • Organizer: 第23回北海道薬物作用談話会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2009-07-11
• [Presentation] エンドセリンA型受容体作動性Ca^<2+>流入に関与するTRPCチャネルの同定 (2009)
  • Author(s): 比嘉綱己
  • Organizer: 第23回北海道薬物作用談話会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2009-07-11
• [Presentation] Molecular analysis of ET_AR-operated Ca^<2+> entry via TRPC channels and visualization of homo-and heterophilic TRPC3/6 interaction in living cells using BiFC (2009)
  • Author(s): Horinouchi T.
  • Organizer: 第26回国際心臓研究学会日本部会
  • Place of Presentation: 北海道大学学術交流会館(北海道)
• [Presentation] Jab1, a ETAR-interacting protein, regulates ETAR level by promoting its degradation (2009)
  • Author(s): Nishimoto A.
  • Organizer: 第26回国際心臓研究学会日本部会
  • Place of Presentation: 北海道大学学術交流会館(北海道)
• [Presentation] エンドセリンA型受容体作動性TRPCチャネルの活性制御機構 (2009)
  • Author(s): 堀之内孝広
  • Organizer: 37回薬物活性シンポジウム
  • Place of Presentation: 東北薬科大学(宮城県)
• [Presentation] 受容体結合蛋白質Jab1によるエンドセリンA型受容体の発現レベル調節機構とその病態的意義 (2009)
  • Author(s): 三輪聡一
  • Organizer: 第37回薬物活性シンポジウム
  • Place of Presentation: 東北薬科大学(宮城県)
• [Presentation] Regulation of cell surface endothelin type A receptor level by anovel receptor-interacting protein, Jabl (2009)
  • Author(s): 西本新
  • Organizer: 第36回国際生理学会世界大会
  • Place of Presentation: 京都国際会議場(京都府)
• [Presentation] Regulation of cell surface endothelin type A receptor level by a novel receptor-interacting protein, Jab1 (2009)
  • Author(s): 西本新
  • Organizer: 第36回国際生理学会世界大会
  • Place of Presentation: 京都国際会議場(京都府)
• [Presentation] Jab1, an ET_AR-interacting protein, regulates ET_AR level by promoting its degradation (2009)
  • Author(s): Nishimoto A
  • Organizer: 第26回国際心臓研究学会日本部会
  • Place of Presentation: 北海道大学学術交流会館(北海道)
• [Presentation] Molecular analysis of ET_AR-operated Ca^<2+> entry via TRPC channels and visualization of homo- and heterophilic TRPC3/6 interaction in living cells using BiFC (2009)
  • Author(s): Horinouchi T
  • Organizer: 第26回国際心臓研究学会日本部会
  • Place of Presentation: 北海道大学学術交流会館(北海道)
• [Remarks]
  • URL: http://saibo-yakuri.med.hokudai.ac.jp/index.html
• [Remarks]
  • URL: http://saibo-yakuri.med.hokudai.ac.jp/index.html
• [Remarks]
  • URL: http://saibo-yakuri.med.hokudai.ac.jp/index.html
• [Remarks]
  • URL: http://saibo-yakuri.med.hokudai.ac.jp/index.html