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Molecular anatomy of photoreceptor ribbon synapses with special attention to the ADP ribosylation factor 6 (Arf6) pathway

Research Project

Project/Area Number 15H04672
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General anatomy (including histology/embryology)
Research InstitutionKitasato University

Principal Investigator

SAKAGAMI HIROYUKI  北里大学, 医学部, 教授 (90261528)

Research Collaborator FUKAYA Masahiro  
HARA Yoshinobu  
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2015: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsリボンシナプス / 視覚 / 筋ジストロフィー / 小胞輸送 / シナプス / 低分子量GTP結合タンパク質 / 網膜 / 光感受細胞 / 視細胞 / 光受容 / 低分子量Gタンパク質 / ジストロフィン
Outline of Final Research Achievements

The aim of this study is to provide the functional importance of the ADP ribosylation factor 6 (Arf6) pathway in the photoreceptor ribbon synapse. By immunofluorescence and immunoelectron microscopy using a novel anti-BRAG2a antibody, we found that BRAG2a, a guanine nucleotide exchange factor specific for Arf6, colocalized to the plasma membrane of lateral walls and processes of photoreceptor terminals within the synaptic cavity with dystroglycan and dystrophin. Pull-down and immunoprecipitation assays using the retinal lysate demonstrated the complex formation of BRAG2a with the dystrophin and beta-dystroglycan. The present study provides evidence for BRAG2a as a novel component of the photoreceptor dystrophin-associated glycoprotein complex (DGC), suggesting the possible functional involvement of the BRAG2a-Arf6 pathway downstream of the DGC in synaptic organization of photoreceptors.

Academic Significance and Societal Importance of the Research Achievements

ヒトの外界からの情報の大半は視覚に依存しており、視覚障害が生活の質(QOL)に与える影響は著しく大きい。網膜の視細胞は、明暗・色調を鋭敏に感知して神経伝達物質を持続的に放出する特殊なシナプス「リボンシナプス」を持つ。しかしながら、リボンシナプスの生理学的特性を支える分子制御機序は未だ不明である。本研究は、低分子量G蛋白質Arf6経路の網膜リボンシナプスでの機能を明らかにするために実施した.
その結果、視細胞リボンシナプスにおいてArf6活性化制御因子BRAG2aがジストロフィン複合体を形成することを見出し、リボンシナプスの形成・維持に関わる新たな制御経路である可能性を示した。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (42 results)

All 2019 2018 2017 2016 2015 Other

All Journal Article (23 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 23 results,  Open Access: 15 results,  Acknowledgement Compliant: 7 results) Presentation (15 results) Remarks (4 results)

  • [Journal Article] Involvement of SRF coactivator MKL2 in BDNF-mediated activation of the synaptic activity-responsive element in the Arc gene.2019

    • Author(s)
      Kikuchi K, Ihara D, Fukuchi M, Tanabe H, Ishibashi Y, Tsujii J, Tsuda M, Kaneda M, Sakagami H, Okuno H, Bito H, Yamazaki Y, Ishikawa M, Tabuchi A.
    • Journal Title

      Journal of Neurochemistry

      Volume: 148 Issue: 2 Pages: 204-218

    • DOI

      10.1111/jnc.14596

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CMT type 2N disease-associated AARS mutant inhibits neurite growth that can be reversed by valproic acid2019

    • Author(s)
      Tatsumi Yuriko、Matsumoto Naoto、Iibe Noriko、Watanabe Natsumi、Torii Tomohiro、Sango Kazunori、Homma Keiichi、Miyamoto Yuki、Sakagami Hiroyuki、Yamauchi Junji
    • Journal Title

      Neuroscience Research

      Volume: 139 Pages: 69-78

    • DOI

      10.1016/j.neures.2018.09.016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells2019

    • Author(s)
      Sakai Y, Kassai H, Nakayama H, Fukaya M, Maeda T, Nakao K, Hashimoto K, Sakagami H, Kano M, Aiba A.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 2799-2799

    • DOI

      10.1038/s41598-019-38730-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pallidin is a novel interacting protein for cytohesin-2 and regulates the early endosomal pathway and dendritic formation in neurons2018

    • Author(s)
      Ito Akiko、Fukaya Masahiro、Saegusa Shintaro、Kobayashi Emi、Sugawara Takeyuki、Hara Yoshinobu、Yamauchi Junji、Okamoto Hirotsugu、Sakagami Hiroyuki
    • Journal Title

      Journal of Neurochemistry

      Volume: 147 Issue: 2 Pages: 153-177

    • DOI

      10.1111/jnc.14579

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FIP4/Arfophilin-2 plays overlapping but distinct roles from FIP3/Arfophilin-1 in neuronal migration during cortical layer formation2018

    • Author(s)
      Hara Yoshinobu、Fukaya Masahiro、Sugawara Takeyuki、Sakagami Hiroyuki
    • Journal Title

      European Journal of Neuroscience

      Volume: 48 Issue: 9 Pages: 3082-3096

    • DOI

      10.1111/ejn.14199

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] New Features on the Expression and Trafficking of mGluR1 Splice Variants Exposed by Two Novel Mutant Mouse Lines.2018

    • Author(s)
      Rika Naito, Hidetoshi Kassai, Yusuke Sakai, Sabine Schönherr, Masahiro Fukaya, Christoph Schwarzer, Hiroyuki Sakagami, Kazuki Nakao, Atsu Aiba, Francesco Ferraguti
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 11 Pages: 439-439

    • DOI

      10.3389/fnmol.2018.00439

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BRAG2a, a guanine nucleotide exchange factor for Arf6, is a component of the dystrophin-associated glycoprotein complex at the photoreceptor terminal.2017

    • Author(s)
      Sakagami H, Katsumata O, Hara Y, Sasaoka T, Fukaya M
    • Journal Title

      Investigative Ophthalmology and Visual Science (IOVS)

      Volume: 58 Issue: 9 Pages: 3795-3803

    • DOI

      10.1167/iovs.17-21746

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cellular and subcellular localization of ADP-ribosylation factor 6 in mouse peripheral tissues2017

    • Author(s)
      Katsumata Osamu、Mori Momoko、Sawane Yusuke、Niimura Tomoko、Ito Akiko、Okamoto Hirotsugu、Fukaya Masahiro、Sakagami Hiroyuki
    • Journal Title

      Histochemistry and Cell Biology

      Volume: 148 Issue: 6 Pages: 577-596

    • DOI

      10.1007/s00418-017-1599-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility.2017

    • Author(s)
      Okuda K, Kobayashi S, Fukaya M, Watanabe A, Murakami T, Hagiwara M, Sato T, Ueno H, Ogonuki N, Komano-Inoue S, Manabe H, Yamaguchi M, Ogura A, Asahara H, Sakagami H, Mizuguchi M, Manabe T, Tanaka T
    • Journal Title

      Neurobiology of Diseases

      Volume: 106 Pages: 158-170

    • DOI

      10.1016/j.nbd.2017.07.002

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Data on the effect of knockout of cytohesin-1 in myelination-related protein kinase signaling.2017

    • Author(s)
      Ruri Tsuneishi, Naoto Matsumoto, Misa Itaoka, Yuki Urai, Minami Kaneko, Natsumi Watanabe, Shou Takashima, Yoichi Seki, Takako Morimoto, Hiroyuki Sakagami, Yuki Miyamoto, and Junji Yamauchi
    • Journal Title

      Data Brief.

      Volume: 15 Pages: 234-239

    • DOI

      10.1016/j.dib.2017.09.024

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Co-localization of endogenous Arf6 and its activator EFA6D in the granular convoluted tubule cells of mouse submandibular glands under normal conditions and when stimulated by isoproterenol, noradrenaline and carbachol.2017

    • Author(s)
      Tachow A, Thoungseabyoun W, Phuapittayalert L, Petcharat K, Sakagami H, Kondo H, Hipkaeo W.
    • Journal Title

      Arch Oral Biol.

      Volume: 82 Pages: 153-159

    • DOI

      10.1016/j.archoralbio.2017.06.007

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Distinct subcellular localization of alternative splicing variants of EFA6D, a guanine nucleotide exchange factor for Arf6, in the mouse brain.2016

    • Author(s)
      Fukaya M, Ohata S, Hara Y, Tamaki H, Sakagami H.
    • Journal Title

      Journal of Comparative Neurology

      Volume: 477 Issue: 13 Pages: 868-873

    • DOI

      10.1002/cne.24048

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Expression of β subunit of Ca2+/calmodulin-dependent protein kinase I in the developing rat retina.2016

    • Author(s)
      Jusuf AA, Sakagami H, Kikkawa S, Terashima T.
    • Journal Title

      Kobe Journal of Medical Sciences

      Volume: 61

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis: Defects in the pathways of amniotic fluid clearance.2016

    • Author(s)
      Tanahashi, H.;Tian, Q.B.; Hara, Y.;Sakagami, H.;Endo, S.;Suzuki, T.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 20241-20241

    • DOI

      10.1038/srep20241

    • NAID

      120007100143

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interaction of serologically defined colon cancer antigen-3 with Arf6 and its predominant expression in the mouse testis.2016

    • Author(s)
      Sakagami H, Hara Y, Fukaya M.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 477 Issue: 4 Pages: 868-873

    • DOI

      10.1016/j.bbrc.2016.06.150

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] ADP ribosylation factor 6 regulates neuronal migration in the developing cerebral cortex through FIP3/Arfophilin-1-dependent endosomal trafficking of N-cadherin.2016

    • Author(s)
      Yoshinobu Hara, Masahiro Fukaya, Kanehiro Hayashi, Takeshi Kawauchi, Kazunori Nakajima, and Hiroyuki Sakagami
    • Journal Title

      eNeuro

      Volume: 3 Issue: 4 Pages: 1-20

    • DOI

      10.1523/eneuro.0148-16.2016

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeted disruption of the mouse protein phosphatase ppm1l gene leads to structural abnormalities in the brain.2016

    • Author(s)
      Kusano, R., Kousuke Fujita, K., Yasuharu Shinoda, Y., Nagaura, Y., Kiyonari, H., Abe, T, Watanabe, T., Matsui, Y., Fukaya, M., Sakagami, H., Sato, T., Funahashi, J.-I., Ohnishi, M., Tamura, S., Kobayashi, T.
    • Journal Title

      FEBS Letters

      Volume: 590 Issue: 20 Pages: 3603-3615

    • DOI

      10.1002/1873-3468.12429

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves.2015

    • Author(s)
      Tomohiro Torii, Nobuhiko Ohno, Yuki Miyamoto, Kazuko Kawahara, Yurika Saitoh, Kazuaki Nakamura, Shou Takashima, Hiroyuki Sakagami, Akito Tanoue, and Junji Yamauchi
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 460 Issue: 3 Pages: 819-825

    • DOI

      10.1016/j.bbrc.2015.03.113

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Arf6 mediates Schwann cell differentiation and myelination.2015

    • Author(s)
      Tomohiro Torii, Yuki Miyamoto, Masahiro Yamamoto, Katsuya Ohbuchi, Hideki Tsumura, Kazuo Kawahara, Akito Tanoue, Hiroyuki Sakagami, and Jyunji Yamauchi
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 465 Issue: 3 Pages: 450-457

    • DOI

      10.1016/j.bbrc.2015.08.038

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Novel splice variants in the 5’UTR of Gtf2i expressed in the rat brain: alternative 5’UTRs and differential expression in the neuronal dendrites.2015

    • Author(s)
      Yoshinori Shirai, Masahiko Watanabe, Hiroyuki Sakagami and Tatsuo Suzuki
    • Journal Title

      J. Neurochemistry

      Volume: 134 Issue: 3 Pages: 578-589

    • DOI

      10.1111/jnc.13136

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice.2015

    • Author(s)
      Moriguchi, S.;Sakagami, H.;Yabuki, Y.;Sasaki, Y.;Izumi, H.;Zhang, C.;Han, F.;Fukunaga, K.
    • Journal Title

      Mol Neurobiol

      Volume: 52 Issue: 3 Pages: 1210-1222

    • DOI

      10.1007/s12035-014-8923-2

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Thromboxane A2 induces blood flow recovery via platelet adhesion to ischaemic regions.2015

    • Author(s)
      Amano H, Ito Y, Eshima K, Kato S, Ogawa F, Hosono K, Oba K, Tamaki H, Sakagami H, Shibuya M, Narumiya S, Majima M.
    • Journal Title

      Cardiovasc Res.

      Volume: 107 Issue: 4 Pages: 509-521

    • DOI

      10.1093/cvr/cvv139

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia.2015

    • Author(s)
      Amano H, Kato S, Ito Y, Eshima K, Ogawa F, Takahashi R, Sekiguchi K, Tamaki H, Sakagami H, Shibuya M, Majima M.
    • Journal Title

      PLoS One

      Volume: 10(7) Issue: 7 Pages: e0131445-e0131445

    • DOI

      10.1371/journal.pone.0131445

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 低分子量Gタンパク質Arf6活性化因子EFA6Cの小脳シナプス形成における役割2019

    • Author(s)
      三枝信太郎、深谷 昌弘 、阪上 洋行
    • Organizer
      第124回日本解剖学会総会・全国学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Arf6活性化制御因子cytohesin 2 の局在解析と疼痛制御機構における役割2019

    • Author(s)
      伊藤諭子、深谷昌弘、岡本浩嗣、阪上洋行
    • Organizer
      第124回日本解剖学会総会・全国学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 大脳皮質層形成におけるArf 結合タンパク質Arfophilin-1 と-2 の機能的差異2018

    • Author(s)
      原芳伸、阪上洋行
    • Organizer
      第106回日本解剖学会関東支部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脊髄におけるCytohesin 2 の局在解析と疼痛制御の機能関与2018

    • Author(s)
      伊藤諭子、深谷昌弘、岡本浩嗣、阪上洋行
    • Organizer
      第106回日本解剖学会関東支部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規cytohesin-2結合分子Pallidinの初期エンドソーム輸送調節と樹状突起形成制御機構2018

    • Author(s)
      深谷 昌弘、伊藤 諭子、三枝信太郎 、原 芳伸、阪上 洋行
    • Organizer
      第123回日本解剖学会総会・全国学術集会(東京)
    • Related Report
      2017 Annual Research Report
  • [Presentation] 中枢神経系髄鞘形成におけるArf6活性調節因子cytohesin-2の機能2017

    • Author(s)
      加倉井俊也, 深谷昌弘, 山内淳司, 阪上洋行
    • Organizer
      第122回日本解剖学会総会・全国学術集会
    • Place of Presentation
      長崎大学坂本キャンパス(長崎県長崎市)
    • Year and Date
      2017-03-28
    • Related Report
      2016 Annual Research Report
  • [Presentation] 新規cytohesin-2結合分子Pallidinの生体マウス脳における細胞内局在解析2017

    • Author(s)
      深谷昌弘, 小林瑛未, 阪上洋行
    • Organizer
      第122回日本解剖学会総会・全国学術集会
    • Place of Presentation
      長崎大学坂本キャンパス(長崎県長崎市)
    • Year and Date
      2017-03-28
    • Related Report
      2016 Annual Research Report
  • [Presentation] 新規cytohesin-2結合分子Pallidinの細胞内局在とその機能2017

    • Author(s)
      深谷 昌弘、伊藤 諭子、岡本 浩嗣、阪上 洋行
    • Organizer
      第40回日本神経科学大会(千葉)
    • Related Report
      2017 Annual Research Report
  • [Presentation] 神経細胞の移動におけるRab11-FIP3,FIP4の機能解析2016

    • Author(s)
      原 芳伸, 阪上 洋行
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-07-20
    • Related Report
      2016 Annual Research Report
  • [Presentation] Arf6活性制御因子BRAG2cはジストロフィン複合体との相互作用を介して網膜視細胞のシナプスに局在する2016

    • Author(s)
      阪上 洋行, 深谷 昌弘
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-07-20
    • Related Report
      2016 Annual Research Report
  • [Presentation] シナプス後部におけるBRAG2-Arf6シグナル経路を介したAMPA受容体輸送調節機構2016

    • Author(s)
      深谷 昌弘, 阪上 洋行
    • Organizer
      第121回日本解剖学会総会・全国学術集会
    • Place of Presentation
      ビックパレットふくしま(郡山市)
    • Year and Date
      2016-03-30
    • Related Report
      2015 Annual Research Report
  • [Presentation] BRAG2-Arf6経路による新たなAMPA受容体シナプス発現調節機構2015

    • Author(s)
      阪上 洋行
    • Organizer
      BMB2015(第86回日本生化学会大会・第38回日本分子生物学会)
    • Place of Presentation
      神戸国際会議場 (神戸市中央区)
    • Year and Date
      2015-11-07
    • Related Report
      2015 Annual Research Report
  • [Presentation] BRAG2はendophilin3との相互作用を介してシナプス後部でのArf6の活性化とAMPA型受容体のエンドサイトーシスを調節する2015

    • Author(s)
      深谷 昌弘, 阪上 洋行
    • Organizer
      第38回日本神経科学大会
    • Place of Presentation
      神戸国際会議場 (神戸市中央区)
    • Year and Date
      2015-07-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] ADPリボシル化因子6 (Arf6)は脳層形成において神経細胞の移動を制御する2015

    • Author(s)
      原 芳伸, 阪上 洋行
    • Organizer
      第38回日本神経科学大会
    • Place of Presentation
      神戸国際会議場 (神戸市中央区)
    • Year and Date
      2015-07-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] グリシン作動性ニューロンでCreを発現するマウス系統の開発2015

    • Author(s)
      柿崎 利和, 阪上 洋行, 崎村 建司, 柳川 右千夫
    • Organizer
      第38回日本神経科学大会
    • Place of Presentation
      神戸国際会議場 (神戸市中央区)
    • Year and Date
      2015-07-28
    • Related Report
      2015 Annual Research Report
  • [Remarks] 北里大学医学部解剖学(阪上)単位ホームページ

    • URL

      http://www.med.kitasato-u.ac.jp/~sakagami/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 北里大学医学部解剖学(阪上)単位ホームページ

    • URL

      http://www.med.kitasato-u.ac.jp/~sakagami/

    • Related Report
      2017 Annual Research Report
  • [Remarks] 北里大学医学部解剖学(阪上)単位ホームページ

    • URL

      http://www.med.kitasato-u.ac.jp/~sakagami/index.php?FrontPage

    • Related Report
      2016 Annual Research Report
  • [Remarks] 北里大学医学部解剖学(阪上)単位ホームページ

    • URL

      http://www.med.kitasato-u.ac.jp/~sakagami/index.php?FrontPage

    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2020-03-30  

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