Effect of anticancer drugs on 5-HT3 receptor subunits

• Project/Area Number: 24659748
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Otorhinolaryngology
• Research Institution: Osaka University
• Principal Investigator: SHIMADA Shoichi 大阪大学, 医学(系)研究科(研究院), 教授 (20216063)
• Co-Investigator(Kenkyū-buntansha): ISHIDA Yusuke 大阪大学, 大学院医学系研究科, 講師 (30381809) ; NAKAMURA Yukiko 大阪大学, 大学院医学系研究科, 助教 (90548083) ; YAMADA Takahiro 大阪大学, 大学院医学系研究科, 助教 (40601597)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 化学療法 / 5-HT3受容体 / 抗がん剤 / セロトニン / 悪心 / 嘔吐 / 抗癌剤

Research Abstract

The 5-hydroxytryptamine (serotonin) type 3 (5-HT3) receptor belongs to the superfamily of Cys-loop ligand-gated ion channels, and can be either homopentameric (5-HT3A) or heteropentameric (5-HT3AB) receptor. We showed that the anticancer drug, topotecan, bidirectionally modulates the 5-HT3 receptor using a voltage clamp technique. Topotecan inhibited 5-HT-gated current through homomeric 5-HT3A receptors. On the other hand, additional expression of the 5-HT3B subunit changed the response to topotecan from an inhibitory to a potentiatory one. Furthermore, the effect was reduced in the receptors containing the 5-HT3B (Y129S) polymorphic variant. These finding could explain individual differences in the sensitivity to topotecan-induced nausea and vomiting.

Research Products

• [Journal Article] 5-HT(3) receptor expression in the mouse vestibular ganglion (2014)
  • Author(s): Takimoto Y, Ishida Y, Nakamura Y, Kamakura T, Yamada T, Kondo M, Kitahara T, Uno A, Imai T, Horii A, Okazaki S, Nishiike S, Inohara H, Shimada S
  • Journal Title: Brain Res Volume: 1157 Pages: 74-82
• [Journal Article] The 5-HT3A receptor is essential for fear extinction (2014)
  • Author(s): Kondo M, Nakamura Y, Ishida Y, Yamada T, Shimada S
  • Journal Title: Learn Mem Volume: 21(1) Pages: 1-4
• [Journal Article] 5-HT3 receptor expression in the mouse vestibular ganglion (2014)
  • Author(s): Takimoto Y, Ishida Y, Nakamura Y, Kamakura T, Yamada T, Kondo M, Kitahara T, Uno A, Imai T, Horii A, Okazaki S, Nishiike S, Inohara H, Shimada S
  • Journal Title: Brain Res Volume: 1557 Pages: 74-82
  • DOI: 10.1016/j.brainres.2014.02.016
  • Peer Reviewed
• [Journal Article] Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan (2013)
  • Author(s): Nakamura Y, Ishida Y, Yamada T, Kondo M, Shimada S
  • Journal Title: J Neurochem Volume: 125(1) Pages: 7-15
• [Journal Article] Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan” Journal of neurochemistry (2013)
  • Author(s): Yukiko Nakamura
  • Journal Title: Journal of neurochemistry Volume: 125(1) Issue: 1 Pages: 7-15
  • DOI: 10.1111/jnc.12146
  • Peer Reviewed
• [Journal Article] The 5-HT3A receptor is essential for fear extinction. (2013)
  • Author(s): Kondo M, Nakamura Y, Ishida Y, Yamada T, Shimada S
  • Journal Title: Learn Mem Volume: 21 Issue: 1 Pages: 1-4
  • DOI: 10.1101/lm.032193.113
  • Peer Reviewed
• [Presentation] 抗癌剤による5- HT3受容体への直接作用 (2014)
  • Author(s): 中村雪子、石田雄介、近藤誠、島田昌一
  • Organizer: 第119回日本解剖学会総会全国学術集会
  • Place of Presentation: 栃木
• [Presentation] 抗癌剤による5-HT3受容体への直接作用 (2014)
  • Author(s): 中村雪子、石田雄介、近藤 誠、島田昌一
  • Organizer: 第１１９回日本解剖学会総会全国学術集会
  • Place of Presentation: 栃木
• [Presentation] Direct modification of 5- HT3 receptor by anti- cancer drugs (2013)
  • Author(s): Yukiko Nakamura, Yusuke Ishida, Makoto Kondo, Shoichi Shimada
  • Organizer: 第56回日本神経科学会大会
  • Place of Presentation: 京都
• [Presentation] 抗癌剤トポテカンによるセロトニン3受容体のサブユニットに依存した応答調節 (2013)
  • Author(s): 中村雪子、石田雄介、山田貴博、近藤誠、島田昌一
  • Organizer: 第118回日本解剖学会総会
  • Place of Presentation: 香川県高松市かがわ国際会議場
• [Presentation] Direct modification of 5-HT3 receptor by anti-cancer drugs. (2013)
  • Author(s): Yukiko Nakamura, Yusuke Ishida, Makoto Kondo, Shoichi Shimada
  • Organizer: 第５６回日本神経科学会大会
  • Place of Presentation: 京都
• [Presentation] 抗癌剤トポテカンによるセロトニン３受容体のサブユニットに依存した応答調節 (2013)
  • Author(s): 中村雪子、石田雄介、山田貴博、近藤誠、島田昌一
  • Organizer: 第118回日本解剖学会総会
  • Place of Presentation: 香川県高松市かがわ国際会議場
• [Presentation] Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan. The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry (2012)
  • Author(s): Y. Nakamura, Y. Ishida, T. Yamada, M. Kondo, S. Shimada
  • Organizer: 55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Kobe, Japan
• [Presentation] Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan (2012)
  • Author(s): Y. Nakamura, Y. Ishida, T. Yamada, M. Kondo, S. Shimada
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry / 55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Kobe, Japan