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

2022 Fiscal Year Final Research Report

• 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
• Keywords: palmitoylation / GPCR / b3-adrenergic receptor

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.

Free Research Field

薬理学関連

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。