GPCR and diseases: mechanisms and therapeutic strategies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08996
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Makita Noriko 東京大学, 医学部附属病院, 准教授 (60353455)
• Co-Investigator(Kenkyū-buntansha): 佐藤 潤一郎 東京大学, 医学部附属病院, 助教 (50552890)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: GPCR / biased agonism / endocrine disease

Outline of Final Research Achievements

Analysis of rare endocrine diseases caused by GPCR signaling disorder has revealed how GPCR signaling can be regulated specifically. In a patient diagnosed with acquired hypocalciuric hypercalcemia, we found unique autoantibodies working as biased allosteric modulators against CaSR and disclosed where they act. In vitro analysis, we found that cinacalcet can overcome the effect of the autoantibodies by working as a positive allosteric modulator, and succeeded in treating the patient with cinacalcet. To explore how biased signaling is constituted in this rare disease, we investigated mechanisms of G protein bias and tried cloning of unique monoclonal antibody against CaSR. These investigations may help us to reveal the unique structure of GPCR which activates a specific signaling and to create a novel drug which activates only a desired signaling.

Free Research Field

内分泌学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、われわれのゲノムで最大のファミリーを形成し、創薬ターゲットの中心となってきたGタンパク質共役受容体（GPCR）の特異的な制御機構の解明に寄与することが期待される。そして、生理的な恒常性維持機構にも関与している可能性、さらには新たな創薬の基盤となる可能性を示唆する。