An analgesic neuropeptide endomorphin may be produced by RNA editing induced by oxidative stress

• Project/Area Number: 26670288
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: Kyushu University
• Principal Investigator: Matsushima Ayami 九州大学, 理学(系)研究科(研究院), 准教授 (60404050)
• Co-Investigator(Kenkyū-buntansha): KOYANAGI KANAKO 北海道大学, 情報科学研究科, 准教授 (20362840)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 遺伝子 / ゲノム / 生体分子 / 脳・神経 / 生理活性 / ペプチド / 疼痛 / 鎮痛

Outline of Final Research Achievements

Endomorphin-1 and -2 are neuropeptides consisting of only 4 amino acid residues. Various biological functions of these peptides are known, for instance analgesic activity that is stronger than that of morphine and a relation with itching. However, to date a precursor protein of these peptides has never been uncovered. Many scientists today consider that the limited information from short peptide sequence makes it difficult to find peptide genes by in silico genomic searches. In the present study, we intended to perform RNA-seq determinations combined with an in silico genomic search for the peptide precursor protein. We succeeded in finding an endomorphin-like peptide, although this was not exactly the same as endomorphins. The synthetic peptide corresponding to the endomorphin-like amino acid sequence has a weak binding affinity for opioid receptors.

Research Products

• [Journal Article] Specific affinity-labeling of the nociceptin ORL1 receptor using a thiol-activated Cys(Npys)-containing peptide ligand. (2016)
  • Author(s): A. Matsushima, H. Nishimura, Y. Matsuyama, X. Liu, T. Costa, and Y. Shimohigashi
  • Journal Title: Biopolymers: Peptide Science Volume: なし Issue: 4 Pages: 460-469
  • DOI: 10.1002/bip.22792
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ORL1 Nociceptin Receptor Response of Opioid Peptides Derived from Proenkephalin Precursor Protein. (2016)
  • Author(s): Motomatsu, Y., Nishimura, H., Matsusyama, Y., Liu, X., Matsushima, A., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2015 Volume: - Pages: 181-182
  • Peer Reviewed
• [Journal Article] GPCR functional role of Phe-269 and Phe-221 in the molecular switching of ORL1 nociceptin receptor activation. (2015)
  • Author(s): Takesue, Y., Nishimura, H., Liu, X., Matsushima, A., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2014 Volume: - Pages: 203-204
  • Peer Reviewed
• [Journal Article] Receptor selectivity and specificity of a series of opioid peptides latent in the proenkephalin precursor protein. (2015)
  • Author(s): Motomatsu, Y., Nishimura, H., Matsumoto, Y., Kuramitsu, Y., Inamine, S., Matsushima, A., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2014 Volume: - Pages: 205-206
  • Peer Reviewed
• [Journal Article] An in silico genomic search of endomorphin-like opioid peptides. (2015)
  • Author(s): atsu, Y., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2014 Volume: - Pages: 281-282
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The molecular switching of ORL1 nociceptin receptor in activation/inactivation. (2015)
  • Author(s): Nishimura, H., Li, J., Isozaki, K., Takesue, Y., Liu, X., Shimohigashi, M., Inamine, S., Matsushima, A., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2014 Volume: - Pages: 201-202
  • Peer Reviewed
• [Journal Article] An in silico genomic search of endomorphin-like opioid peptides (2015)
  • Author(s): Matsushima, A., Koyanagi, O.K., Nishimura, H., Inamine, S., Motomatsu, Y., and Shimohigashi. Y.
  • Journal Title: Peptide Science 2014 Volume: - Pages: 201-202
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-Methylthioacetylation of RYYRIK-NH2 with enhanced specific binding affinity and high antagonist activity for nociceptin ORL1 receptor (2014)
  • Author(s): J. Li, H. Nishimura, A. Matsushima, and Y. Shimohigashi
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 22 Issue: 21 Pages: 5721-5726
  • DOI: 10.1016/j.bmc.2014.09.049
  • Peer Reviewed
• [Journal Article] Tritium-Labelled Isovaleryl-RYYRIK-NH2 as Potential Antagonist Probe for ORL1 Nociceptin Receptor (2014)
  • Author(s): S. Inamine, H. Nishimura, J. Li, K. Isozaki, A. Matsushima, T. Costa, and Y. Shimohigashi
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 22 Issue: 21 Pages: 5902-5909
  • DOI: 10.1016/j.bmc.2014.09.018
  • Peer Reviewed
• [Journal Article] Multiple and Simultaneous Cys→Ala Mutations of ORL1 Nociceptin Receptor to Identify the Affinity Binding site of Cys(Npys)-Elongated RYYRIK Peptide Antagonist (2014)
  • Author(s): Matsushima, A., Nishimura, H., Inamine, S., and Shimohigashi, Y.
  • Journal Title: Peptide Science 2013 Volume: - Pages: 413-4144
  • Peer Reviewed
• [Journal Article] Structure-activity Studies on the Halogenated Phe-containing Neuropeptide Substance P Analogs (2014)
  • Author(s): Kuramitsu, Y., Nishimura, H., Nakamura, R., Suyama, K., Matsushima, A., Nose, T., and Shimohigashi, Y.
  • Journal Title: Peptide Science 2013 Volume: - Pages: 319-320
• [Journal Article] Specific Role of Phe Residues in Opioid Peptide Met-enkephalin- Arg-Phe in Binding to All Three Opioid Receptors (2014)
  • Author(s): Motomatsu, Y., Nishimura, H., Matsumoto, Y., Inamine, S., Kuramitsu, Y., Matsushima, A., and Shimohigashi, Y.
  • Journal Title: Peptide Science 2013 Volume: - Pages: 317-318
• [Presentation] プロエンケファリン前駆体からプロセッシングされる全オピオイドペプチドの受容体サブタイプ特異性 (2015)
  • Author(s): 元松 雄大・西村 裕一・松本 結香・蔵満 由美・稲嶺 翔吾・劉 暁輝・松島 綾美・下東 康幸
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（神戸市）
  • Year and Date: 2015-12-01
• [Presentation] ORL1疼痛受容体活性化における新規な分子スイッチ (2015)
  • Author(s): 武末祐貴、西村裕一、劉 暁輝、松島綾美、下東康幸
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（神戸市）
  • Year and Date: 2015-12-01
• [Presentation] ORL1 nociceptin receptor response of opioid peptides derived from proenkephalin precursor protein (2015)
  • Author(s): Yudai Motomatsu, Hirokazu Nishimura, Yutaka Matsuyama, Xiaohui Liu, Ayami Matsushima, and Yasuyuki Shimohigashi
  • Organizer: 第52回ペプチド討論会
  • Place of Presentation: 平塚市中央公民館（平塚市）
  • Year and Date: 2015-11-16
• [Presentation] Functional Role of the Phe-Phe Stacking Microswich in the ORL1 nociceptin receptor activation (2015)
  • Author(s): uuki Takesue, Hirokazu Nishimura, Xiaohui Liu, Ayami Matsushima, and Yasuyuki Shimohigashi
  • Organizer: 第52回ペプチド討論会
  • Place of Presentation: 平塚市中央公民館（平塚市）
  • Year and Date: 2015-11-16
• [Presentation] 痛み増強受容体ORL1のPhe269は受容体活性化における新規な分子スイッチ (2015)
  • Author(s): 武末祐貴、西村裕一、劉 暁輝、松島綾美、下東康幸
  • Organizer: 平成27年度日本生化学会九州支部例会
  • Place of Presentation: 九州大学箱崎キャンパス（福岡市）
  • Year and Date: 2015-05-16
• [Presentation] プロエンケファリン前駆体タンパク質から産生されるオピオイドペプチドのオピオイド受容体サブタイプ選択性と活性化能 (2015)
  • Author(s): 元松雄大、西村裕一、松本結香、蔵満由美、稲嶺翔吾、劉 暁輝、松島綾美、下東康幸
  • Organizer: リスクサイエンス研究フォーラム2014
  • Place of Presentation: 福岡大学セミナーハウス、福岡市
  • Year and Date: 2015-03-09
• [Presentation] An in silico genomic serch of endomorphin-like opioid peptides (2014)
  • Author(s): 松島綾美、小柳香奈子、西村裕一、稲嶺翔吾、元松雄大、下東康幸
  • Organizer: 第51回ペプチド討論会
  • Place of Presentation: 徳島大学蔵本キャンパス大塚講堂、徳島市
  • Year and Date: 2014-10-22 – 2014-10-24
• [Presentation] GPCR functional role of Phe-269 and Phe-221 in the molecular switching of ORL1 nociceptin receptor activation (2014)
  • Author(s): 武末祐貴、西村裕一、劉暁輝、松島綾美、下東康幸
  • Organizer: 第51回ペプチド討論会
  • Place of Presentation: 徳島大学蔵本キャンパス大塚講堂、徳島市
  • Year and Date: 2014-10-22 – 2014-10-24
• [Presentation] ORL1・ノシセプチン受容体活性化における221位および269位Pheの構造要因 (2014)
  • Author(s): 武末祐貴、西村裕一、劉 暁輝、松島綾美、下東康幸
  • Organizer: 第51回化学関連支部合同九州大会
  • Place of Presentation: 北九州国際会議場、北九州市
  • Year and Date: 2014-06-28
• [Presentation] Met-enkephalin-Arg-Pheの４位および７位Phe-フェニル基の異なるオピオイド受容体相互作用性 (2014)
  • Author(s): 元松雄大、西村裕一、松本結香、稲嶺翔吾、蔵満由美、松島綾美、下東康幸
  • Organizer: 第51回化学関連支部合同九州大会
  • Place of Presentation: 北九州国際会議場、北九州市
  • Year and Date: 2014-06-28
• [Remarks] 構造機能生化学（研究室ホームページ）
  • URL: http://lsfb.scc.kyushu-u.ac.jp
• [Remarks] 九州大学大学院理学研究院化学部門大学院理学府化学専攻構造機能生化学研究室
  • URL: http://lsfb.scc.kyushu-u.ac.jp
• [Remarks] 九州大学大学院理学研究院リスクサイエンス研究教育拠点
  • URL: http://rsrc.scc.kyushu-u.ac.jp/index.html