Mechanisms for AMPA-type glutamate receptor anchoring at the synapse

• Project/Area Number: 15H04279
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: FUKATA Yuko 生理学研究所, 分子細胞生理研究領域, 准教授 (40416186)
• Research Collaborator: YOKOI Norihiko 生理学研究所, 分子細胞生理研究領域, 助教 (50710969) ; HIRATA Tetsuya 生理学研究所, 分子細胞生理研究領域, 特任助教 (90780651) ; TAKAHASHI Naoki ; INAHASHI Hiroki ; SEKIYA Atsushi ; MURAKAMI Tatsuro ; FURUKAWA Sachiko ; SUZUKI Yumi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2017: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2015: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: シナプス / AMPA受容体 / グルタミン酸受容体 / パルミトイル化脂質修飾 / PSD-95 / てんかん / 脱パルミトイル化 / ナノドメイン / 脱パルミトイル化酵素 / パルミトイル化 / LGI1 / 神経科学 / 脳神経疾患 / 生理学 / 蛋白質 / 遺伝学 / 超解像顕微鏡 / NMDA受容体

Outline of Final Research Achievements

AMPA-type glutamate receptor (AMPAR) mediates most of fast synaptic transmission in the brain. Although AMPAR dynamically enters and exits the postsynaptic membrane in a synaptic activity-dependent manner, the underlying molecular mechanism is still incompletely understood. In this study, we focused on palmitoylation and protein-protein interactions of PSD-95, an essential scaffolding protein for AMPAR. We discovered a novel enzyme, ABHD17, which catalyzes PSD-95 depalmitoylation and thereby plays an important role in the (re)organization of the postsynaptic platform for AMPAR anchoring. We also found that the epilepsy-related ligand/receptor complex of LGI1 and ADAM22 regulates AMPAR functions through the direct interaction with PSD-95. Furthermore, we revealed the structural basis of the LGI1-ADAM22 protein complex at the synapse and its patho-physiological role in epileptogenesis.

Research Products

• [Int'l Joint Research] Institut Curie/University Paris 7(France)
• [Int'l Joint Research] DZNE(Germany)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Int'l Joint Research] UCSF(U.S.A.)
• [Int'l Joint Research] University of California, San Francisco(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Int'l Joint Research] DZNE(Germany)
• [Int'l Joint Research] University of California, San Francisco(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata A, Miyazaki Y, Yokoi N, Shigematsu H, Sato Y, Goto-Ito S, Maeda A, Goto T, Sanbo M, Hirabayashi M, Shirouzu M, Fukata Y, Fukata M, Fukai S
  • Journal Title: Nat Commun Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Neurobiology of autoimmune encephalitis. (2018)
  • Author(s): Fukata M, Yokoi N, Fukata Y.
  • Journal Title: Curr Opin Neurobiol Volume: 48 Pages: 1-8
  • DOI: 10.1016/j.conb.2017.07.012
  • Peer Reviewed
• [Journal Article] パルミトイル化修飾酵素を軸とした神経機能研究 (2018)
  • Author(s): 平田 哲也，深田 優子，深田 正紀
  • Journal Title: 生化学 Volume: 90
  • NAID: 40021617357
  • Peer Reviewed
• [Journal Article] Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ-independent manner and an amino acid residue at the slide helix governs the activation. (2017)
  • Author(s): Chen, I.S., Tateyama, M., Fukata, Y., Uesugi, M., & Kubo, Y.
  • Journal Title: Journal of Physiology Volume: 595 Issue: 17 Pages: 5895-5912
  • DOI: 10.1113/jp274871
  • Peer Reviewed
• [Journal Article] In situ screening for postsynaptic cell adhesion molecules during synapse formation. (2017)
  • Author(s): Uemura T, Maeda A, Yasumura M, Shimada T, Fukata Y, Fukata M, Yoshida T
  • Journal Title: Journal of Biochemistry Volume: 印刷中 Pages: 295-302
  • DOI: 10.1093/jb/mvx030
  • NAID: 40021380573
  • Peer Reviewed
• [Journal Article] Coupling of a voltage-gated Ca2+ channel homologue with a plasma membrane H+-ATPase in yeast (2017)
  • Author(s): Cho T, Ishii-Kato A, Fukata Y, Nakayama Y, Iida K, Fukata M, Iida H
  • Journal Title: Genes Cells Volume: 22 Issue: 1 Pages: 94-104
  • DOI: 10.1111/gtc.12458
  • Peer Reviewed / Open Access
• [Journal Article] Epilepsy and synaptic proteins (2017)
  • Author(s): Fukata Y, Fukata M
  • Journal Title: Curr Opin Neurobiol Volume: 45 Pages: 1-8
  • DOI: 10.1016/j.conb.2017.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders (2017)
  • Author(s): Fukata Y, Yokoi N, Miyazaki Y, Fukata M
  • Journal Title: Neurosci Res Volume: 116 Pages: 39-45
  • DOI: 10.1016/j.neures.2016.09.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of PSD-95 depalmitoylating enzymes (2016)
  • Author(s): Yokoi N*, Fukata Y*, Sekiya A, Murakami T, Kobayashi K, Fukata M
  • Journal Title: J Neurosci Volume: 36 Issue: 24 Pages: 6431-6444
  • DOI: 10.1523/jneurosci.0419-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy (2016)
  • Author(s): Muona M, Fukata Y, Anttonen AK, Laari A, Palotie A, Pihko H, Lönnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki AE
  • Journal Title: Neurol Genet Volume: 2 Issue: 1
  • DOI: 10.1212/nxg.0000000000000046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Local palmitoylation cycles and specialized membrane domain organization (2016)
  • Author(s): Fukata Y, Murakami T, Yokoi N, Fukata M
  • Journal Title: Curr Top Membr Volume: 77 Pages: 97-141
  • DOI: 10.1016/bs.ctm.2015.10.003
  • Peer Reviewed
• [Journal Article] The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function (2015)
  • Author(s): Lovero KL, Fukata Y, Grangera AJ, Fukata M, Nicoll RA
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 30
  • DOI: 10.1073/pnas.1511910112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synaptic nanodomains generated by local palmitoylation cycles (2015)
  • Author(s): Masaki Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Yuko Fukata
  • Journal Title: Biochemical Society Transactions Volume: 43(2) Issue: 2 Pages: 199-204
  • DOI: 10.1042/bst20140238
  • Peer Reviewed
• [Presentation] Epilepsy-related ligand-receptor, LGI1 and ADAM22: from disease-causing mutations to molecular functions and therapeutic strategies (2017)
  • Author(s): Yuko Fukata
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: 浜松アクトシティコングレスセンター、浜松市、静岡県
  • Year and Date: 2017-03-28
  • Invited
• [Presentation] Assessment of palmitoylation status and cycles on PSD-95 in neurons and in vivo (2017)
  • Author(s): Fukata Y, Yokoi N, Kobayashi K, and Fukata M
  • Organizer: 13th International congress of Polish Neuroscience Society
  • Int'l Joint Research
• [Presentation] Assessment of palmitoylation status and cycles on PSD-95 in neurons and in vivo (2017)
  • Author(s): Fukata Y, Yokoi N, Kobayashi K, and Fukata M
  • Organizer: 5th Annual iGluR Retreat
  • Int'l Joint Research
• [Presentation] PSD organization regulated by PSD-95 palmitoylation machinery (2016)
  • Author(s): Yuko Fukata, Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Kenta Kobayashi, Masaki Fukata
  • Organizer: 10th Forum of Neuroscience (FENS)
  • Place of Presentation: Bella Center, Copenhagen, Denmark
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] Genetic and acquired brain disorders due to dysfunction of an epilepsy-related LGI1 (2016)
  • Author(s): Yuko Fukata
  • Organizer: Invited lecture at Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
  • Place of Presentation: Magdeburg, Germany
  • Invited
• [Presentation] ケミカルシャペロンによるてんかん原因遺伝子産物 LGI1 構造異常の修復 (2015)
  • Author(s): Yuko Fukata
  • Organizer: 第10回 臨床ストレス応答学会大会
  • Place of Presentation: 東京農工大学140周年記念会館（東京都小金井市）
  • Year and Date: 2015-11-06
  • Invited
• [Presentation] Molecular pathogenic mechanisms of epilepsy caused by LGI1 mutations (2015)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martin Jaegle, Keiji Imoto, Deis Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: 45th annual meeting of the Society for Neuroscience
  • Place of Presentation: McCormick Place, Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Exploration of depalmitoylating enzymes regulating bi-directional trafficking of small GTPase HRas (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Yuko Fukata, Masaki Fukata
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-07-28
• [Presentation] Postsynaptic nanodomains organized by local palmitoylation machinery (2015)
  • Author(s): Yuko Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Kenta Kobayashi, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Stoichiometric analysis of palmitoylation cycles on PSD-95 (2015)
  • Author(s): Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein Lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Characterization of a mouse model with genetic deletion of DHHC2 palmitoyl acyl transferase (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Manabu Abe, Kenji Sakimura, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Book] メンブレントラフィック (2016)
  • Author(s): 深田優子、横井紀彦、宮崎裕理、深田正紀
  • Publisher: 化学同人
• [Book] 細胞工学 (2015)
  • Author(s): 横井紀彦、深田正紀、深田優子
  • Publisher: 秀潤社
• [Remarks] 自然科学研究機構 生理学研究所 生体膜研究部門ホームページ
  • URL: http://www.nips.ac.jp/fukata/
• [Remarks] シナプス蛋白質PSD-95の局在を調節する酵素の同定
  • URL: http://www.nips.ac.jp/nips_research/2016/06/psd-95.html
• [Remarks] 生理学研究所 生体膜研究部門ホームページ
  • URL: http://www.nips.ac.jp/fukata/