Research and application of allosteric ligands directed to G-protein coupled receptor heteromers

• Project/Area Number: 24590327
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Jichi Medical University
• Principal Investigator: KOSHIMIZU Taka-aki 自治医科大学, 医学部, 准教授 (20392491)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 薬物受容体 / ヘテロマー複合体 / 受容体 / 選択性 / ペプチドリガンド / 受容体（米国） / 複合体形成 / モルヒネ作用（米国） / オピオイド受容体 / ヘテロマー受容体 / 発現組織分布

Outline of Final Research Achievements

Members of G-protein coupled receptor family proteins have been drug targets of more than 30% of medicines currently used in clinics. It has been turned out that G-protein coupled receptors (GPCRs) exist as dimers or oligomers, in which homomeric as well as heteromeric receptor complex can be formed. There is no method to control GPCR heteromer function allosterically. We searched for new heteromer opioid receptor by developing new evaluation method. Our data indicated that opioid efficacy and side effects could be modulated though heteromer receptors.

Research Products

• [Journal Article] Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide (2015)
  • Author(s): Arai K, Kashiwazaki A, Fujiwara Y, Tsuchiya H, Sakai N, Shibata K, Koshimizu TA3
  • Journal Title: Eur J Pharmacol Volume: 749 Pages: 98-106
  • DOI: 10.1016/j.ejphar.2015.01.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts (2013)
  • Author(s): Tamaki Y, Iwanaga Y, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Horie T, Morooka H, Takase T, Akahashi Y, Kobuke K, Ono K, Shioi T, Sheikh SP, Ambartsumian N, Lukanidin E, Koshimizu TA, Miyazaki S, Kimura T
  • Journal Title: J Mol Cell Cardiol Volume: 57 Pages: 72-81
  • DOI: 10.1016/j.yjmcc.2013.01.007
  • Peer Reviewed
• [Journal Article] Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. (2013)
  • Author(s): Tsuchiya H, Sato J, Tsuda H, Fujiwara Y, Yamada T, Fujimura A, Koshimizu TA.
  • Journal Title: Toxicology Volume: 305 Pages: 79-88
  • DOI: 10.1016/j.tox.2013.01.012
  • Peer Reviewed
• [Journal Article] α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs. (2013)
  • Author(s): Kumazaki M
  • Journal Title: Eur J Pharmacol Volume: 705 Issue: 1-3 Pages: 1-10
  • DOI: 10.1016/j.ejphar.2013.02.027
  • Peer Reviewed
• [Journal Article] Voluntary locomotion linked with cerebral activation is mediated by vasopressin V1a receptors in free-moving mice (2012)
  • Author(s): Masuki S, Sumiyoshi E, Koshimizu T, Qian J, Higuchi K, Tsujimoto G, and Nose H
  • Journal Title: J Physiol (Lond.) Volume: (in press) Issue: 14 Pages: 3651-3665
  • DOI: 10.1113/jphysiol.2013.251876
  • Peer Reviewed
• [Journal Article] Vasopressin V1a and V1b receptors: from molecules to physiological systems (2012)
  • Author(s): T.A. Koshimizu, K. Nakamura, N. Egashira, M. Hiroyama, H. Nonoguchi, A. Tanoue
  • Journal Title: Physiological reviews Volume: 92 Issue: 4 Pages: 1813-1864
  • DOI: 10.1152/physrev.00035.2011
  • Peer Reviewed
• [Journal Article] Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human (2012)
  • Author(s): Ichimura A
  • Journal Title: Nature Volume: 483 Issue: 7389 Pages: 350-354
  • DOI: 10.1038/nature10798
  • Peer Reviewed
• [Journal Article] Chronic ritodrine treatment induces refractoriness of glucose-lowering beta2 adrenoceptor signal in female mice (2012)
  • Author(s): Tsuchiya H., et.al.
  • Journal Title: Regulatory toxicology and pharmacology Volume: 62 Issue: 3 Pages: 561-567
  • DOI: 10.1016/j.yrtph.2011.11.011
  • Peer Reviewed
• [Journal Article] The roles of V1a vasopressin receptors in blood pressure homeostasis : a review of studies on V1a receptor knockout mice (2012)
  • Author(s): Fujiwara Y, et.al.
  • Journal Title: Clinical and experimental nephrology Volume: 16 Issue: 1 Pages: 30-34
  • DOI: 10.1007/s10157-011-0497-y
  • Peer Reviewed
• [Presentation] V1bバゾプレッシン受容体複合体の機能解析 (2015)
  • Author(s): 輿水崇鏡、本多健治、高野行夫
  • Organizer: バゾプレッシン研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-01-10
• [Presentation] V1bバゾプレッシン受容体内在化機構の解明と制御 (2014)
  • Author(s): 柏﨑亜樹、藤原葉子、土屋裕義、輿水崇鏡
  • Organizer: 第130回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-05
• [Presentation] Functional Interaction between V1b Vasopressin and MOR1 Opioid Receptors Delays Development of Morphine Tolerance and Adenylate Cyclase Sensitization (2014)
  • Author(s): Taka-aki Koshimizu, Kenji Honda, Yukio Takano
  • Organizer: 第87回日本薬理学会
  • Place of Presentation: 仙台
• [Presentation] 下垂体後葉ホルモンによるアデニレートサイクラーゼシグナルの調節機構 (2014)
  • Author(s): 輿水崇鏡
  • Organizer: 第14回バゾプレッシン研究会
  • Place of Presentation: 東京
• [Presentation] オピオイド鎮痛におけるバゾプレッシンの役割について (2013)
  • Author(s): 輿水崇鏡、本多健治、高野行夫
  • Organizer: 第２３回バゾプレッシン研究会
  • Place of Presentation: 慶応義塾大学
• [Presentation] 合成サブスタンスPアンタゴニストの広域性とシグナル制御機構 (2012)
  • Author(s): 荒井和音、輿水崇鏡
  • Organizer: 第126回日本薬理学会関東部会
  • Place of Presentation: 北里大学
• [Remarks] 自治医科大学薬理学講座分子薬理学部門
  • URL: http://www.jichi.ac.jp/molpharm/