The mechanism for maintaining long-term activation of the protein kinase CaMKII

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06576
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43040:Biophysics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ode Koji 東京大学, 大学院医学系研究科(医学部), 講師 (40612122)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: タンパク質リン酸化 / CaMKII / キナーゼ

Outline of Final Research Achievements

CaMKIIα/β, a protein kinase that regulates its activity through autophosphorylation, is known to potentially store the history of neural activity as molecular activity. In this study, we investigated how CaMKIIα/β maintains its enzymatic activity following activation by Ca2+/CaM for a relatively long time duration. We utilized an 293T cell extract system to measure the kianse activity of CaMKIIα/β without protein purification. Our measurement revealed that the kinase activity of CaMKIIα/β was suppressed around 30 to 60 minutes after the Ca2+/CaM-dependent activation, and this suppression mechanism is distinct from the known inhibitory autophosphorylation. Furthermore, we found metabolites and specific residues of CaMKIIα/β that control the suppression of CaMKIIα/β activity.

Free Research Field

生化学、生物物理学、時間生物学

Academic Significance and Societal Importance of the Research Achievements

CaMKIIは特徴的な自己リン酸化に依存した自律的活性制御機構の存在から、“記憶分子”としてシナプス可塑性への寄与が深く研究されてきた。しかし、CaMKIIのリン酸化活性を直接測定する生化学研究の多くは、反応初速度測定や定常状態でのCaMKII-CaM相互作用測定に基づいており、CaMKIIのリン酸化活性持続時間を経時的に見積もった実験は多くない。今回、CaMKIIの活性維持機構について、既知の自己リン酸化とは異なるメカニズムの存在を示し、それに関わるCaMKII残基を見出したことで、睡眠覚醒など比較的長い時間スケールの生理現象とCaMKII活性を結び付けるための、新しい観点を提示できた。