核受容体Rev-erbalphaは,日中時計のリチウムに敏感な重要な構成要素である

Lei Yin¹, Jing Wang, Peter S Klein

¹Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

Science (New York, N.Y.)

|February 18, 2006

まとめ

リチウム治療は,日中時計タンパク質のRev-erbalphaを劣化させ,Bmal1遺伝子を活性化させます. この発見は,リチウムの重要なメカニズムを明らかにしています.

科学分野:

クロノバイオロジークロノバイオロジー
分子薬理学分子薬理学
神経精神病学は神経精神病学である.

背景:

双極性障害は,昼夜リズムが乱れていることと関連しています.
リチウムは,一般的な双極性障害の治療法であり,グリコゲン合成キナーゼ3 (GSK3) を阻害する.
GSK3は,様々な生物の昼夜リズムを調節する.

研究の目的:

リチウム,GSK3,および昼夜リズム調節を結びつける分子メカニズムを調査する.
昼間の時計のコンポーネントの安定化におけるGSK3βの役割を決定するためにRev-erbalpha.
リチウムのRev-erbalphaの安定性への影響と,時計遺伝子発現への影響について調べる.

主な方法:

培養細胞を用いて,タンパク質とタンパク質の相互作用と分解経路を調べました.
GSK3βがRev-erbalpha.に与えるリン酸化と安定化の効果を研究した.
リチウム治療がRev-erbalphaレベルとBmal1遺伝子発現に与える影響を評価した.
リチウム無感のRev-erbalpha変異体を使って実験し,その機能を理解した.

主要な成果:

GSK3βは,日中時計タンパク質Rev-erbalphaをリン酸化し,安定させることが判明しました.
リチウム治療は,培養細胞におけるRev-erbalphaの急速なプロテアソマル分解を誘発した.
Rev-erbalphaの分解は,日中時計遺伝子Bmal1.1の活性化につながった.
リチウム無感のRev-erbalpha変異体は,日中活動中の遺伝子発現を妨害し,その調節作用を確認した.

結論:

Rev-erbalphaタンパク質の安定性は,周辺の昼間の時計の重要な調節因子である.
リチウム療法のメカニズムは,Rev-erbalpha.の標的化された分解を伴う.
この研究では,リチウムのサーカディアンリズム調節における治療効果の重要な生物学的標的としてRev-erbalphaを特定しています.

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