Novel regulatory mechanism of cerebellar motor learning via heterologous GPCR coupling

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K22745
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Juntendo University
• Principal Investigator: Sakairi Hakushun 順天堂大学, 医学部, 助教 (20876693)
• Project Period (FY): 2020-09-11 – 2024-03-31
• Keywords: 異種GPCR間相互作用 / 運動学習 / LTD(長期抑圧) / 1型代謝型グルタミン酸受容体(mGluR1) / GABA-B受容体(GBR)

Outline of Final Research Achievements

In this study, we investigated the activation of type 1 metabotropic glutamate receptors (mGluR1) and the phenomenon of long-term depression (LTD) of Purkinje cells that is triggered by mGluR1, which is one of the crucial mechanisms of cerebellar motor learning. Based on the phenomenon that GABA-B receptors (GBRs) are co-expressed at mGluR1-expressed synapses and enhance LTD, we aimed to elucidate the mechanism of LTD enhancement from the viewpoint of changes in the binding state of mGluR1 and GBRs. Using HEK293 cells that co-express mGluR and GBR and primary cultured neurons, we found an association between mGluR1 expression and GBR signaling, and also discovered that one of the subtypes of mGluR is significantly different from mGluR1 in their binding potential to GBR.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

運動学習とは運動の反復によって動きの滑らかさや正確性が獲得される学習過程のことであり、小脳疾患における運動や発話の障害にも関与する重要な機能である。mGluR1はその学習の成立に重要な役割を持つ受容体である。本研究は、そのような重要な役割を持つmGluR1が他のGタンパク質共役型受容体(GPCR)と結合することで相互に機能調節を行う可能性を示すものであり、運動学習やその異常に関して新たな視点を与える学術的意義を持つ。GPCRの相互作用は新たな創薬ターゲットとしても注目されており、本研究もまたmGluR1とGBRの結合と相互作用に基づく運動学習の病態理解や治療戦略を考える上で社会的な意義を持つ。