| Project/Area Number |
17K07333
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
Kasai Rinshi 京都大学, ウイルス・再生医科学研究所, 助教 (20447949)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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| Keywords | 細胞内1分子計測 / Gタンパク質共役型受容体 / ダイマー形成 / G蛋白質共役型受容体 / 蛍光１分子観察 / リガンド刺激 / 動的 / 人工ダイマー / １分子計測（SMD） / 生物物理 / シグナル伝達 / 生理学 / バイオテクノロジー |
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| Outline of Final Research Achievements |
G-protein coupled receptors (GPCRs) constitute the largest receptor family. Recently, it has been found that some species of class A-GPCRs form transient dimers in the plasma membrane. However, the function and significance of dimerization of GPCR remain unclear.
By employing dual-color single fluorescent-molecule observation technique in live cells, we succeeded in directly observing trimeric G-protein recruitment to both GPCR monomer and dimer at a 30 Hz. We also found that inverse agonists inhibit G-protein recruitment only to dimer, suggesting that the transient dimer generates the constitutive activity of GPCR (a weak signaling activity that does not depend on ligand binding). Moreover, it was also found that dimerization of GPCR itself has a signaling activity because cytosolic calcium concentration was elevated by artificially inducing GPCR dimerization. These results suggest that both dimerization and ligand binding cooperate to generate biological signals in live cells.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって、長年未解明であった、Gタンパク質共役型受容体（GPCR）の一過的なダイマー形成の意義の一端が明らかになった。すなわち、一過的なダイマーを形成することで、リガンド結合に依存しないGPCRの弱いシグナル活性を生じること、ダイマー形成が安定化することで、シグナルを生じること、また、リガンド結合とダイマー形成が組み合わさることでシグナル生成を行うらしいことがはじめて明らかになった。
本発見によって、GPCRのシグナル制御に関連する、創薬等に新しい概念がもたらされると考えられる。
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