Exploration of the impact of beta3 adrenergic receptor gene polymorphism on overactive bladder(Fostering Joint International Research)

• Project/Area Number: 16KK0181
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Kobe University
• Principal Investigator: Adachi Naoko 神戸大学, バイオシグナル総合研究センター, 助教 (70604510)
• Project Period (FY): 2017 – 2022
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: palmitoylation / GPCR / b3-adrenergic receptor / ADRB3 / 翻訳後修飾 / パルミトイル化修飾 / 薬理学 / βアドレナリン受容体 / 遺伝子多型

Outline of Final Research Achievements

The beta3 adrenergic receptor (beta3AR) was analyzed for its impact on overactive bladder, with the purpose of exploring treatment methods. Particularly, attention was focused on the role of adrenaline and nitric oxide (NO) in the relaxation/contraction of the bladder during urinary storage/voiding. NO was found to reduce the metabolic turnover of palmitoylation modification in beta3AR, through the inactivation of DHHC protein, an enzyme responsible for palmitoylation modification, as well as the de-palmitoylation enzyme. Consequently, this led to a decrease in receptor expression on the cytoplasmic membrane of beta3AR and a reduction in downstream cyclic adenosine monophosphate (cAMP) production. It has been discovered that the effects of NO extend beyond vasodilation, impacting various palmitoylation-modified proteins, including human beta3AR.

Academic Significance and Societal Importance of the Research Achievements

本研究によりヒトとマウスのベータ３アドレナリン受容体の機能的違いが、脂質翻訳後修飾であるパルミトイル化修飾によって引き起こされていることが明らかとなった。パルミトイル化修飾はヒトベータ３アドレナリン受容体の細胞質膜への発現を安定化させることで、細胞外からの応答性を増加している。この調節機構はマウスの受容体では見られず、疾患モデルを用いた研究では野生型マウスの使用は適していない。本研究ではヒトのベータ３アドレナリン受容体を発現するマウスの作製を行い、よりヒトの疾患に適した病態モデルマウスの作製を可能とすることを目指している。

Research Products

• [Int'l Joint Research] Case Western Reserve University(米国) (2017)
  • Year and Date: 2017-08-10
• [Journal Article] S-Palmitoylation of Tyrosinase at Cysteine500 Regulates Melanogenesis (2023)
  • Author(s): Niki Yoko、Adachi Naoko、Fukata Masaki、Fukata Yuko、Oku Shinichiro、Makino-Okamura Chieko、Takeuchi Seiji、Wakamatsu Kazumasa、Ito Shosuke、Declercq Lieve、Yarosh Daniel B.、Mammone Tomas、Nishigori Chikako、Saito Naoaki、Ueyama Takehiko
  • Journal Title: Journal of Investigative Dermatology Volume: 143 Issue: 2 Pages: 317-327.e6
  • DOI: 10.1016/j.jid.2022.08.040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S-nitrosylation is required for β2AR desensitization and experimental asthma (2022)
  • Author(s): Fonseca Fabio V.、Raffay Thomas M.、Xiao Kunhong、McLaughlin Precious J.、Qian Zhaoxia、Grimmett Zachary W.、Adachi Naoko、Wang Benlian、Hausladen Alfred、Cobb Brian A.、Zhang Rongli、Hess Douglas T.、Gaston Benjamin、Lambert Nevin A.、Reynolds James D.、Premont Richard T.、Stamler Jonathan S.
  • Journal Title: Molecular Cell Volume: 82 Issue: 16 Pages: 3089-3102.e7
  • DOI: 10.1016/j.molcel.2022.06.033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] チロシナーゼのパルミトイル化修飾によるメラニン合成制御機構 (2022)
  • Author(s): 仁木洋子、足立直子、深田正紀、深田優子、錦織千佳子、齋藤尚亮、上山健彦
  • Organizer: 第141回日本薬理学会 近畿部会