CRTC1-SIK1経路は,日中時計の誘導を調節する
Aarti Jagannath1, Rachel Butler1, Sofia I H Godinho1
1Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), University of Oxford, Levels 5-6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK; pRED Pharma Research and Development F. Hoffmann-La Roche, 4070 Basel, Switzerland.
Cell
|September 3, 2013
まとめ
塩誘導キナーゼ1 (SIK1) は,cAMP応答要素結合タンパク質 (CREB) 経路を阻害することによって,昼間の時計のリセットを調節する. SIK1の減少は,ジェットラグ後の再トレーニングを加速し,昼夜リズム調節のためのターゲットを提供します.
科学分野:
- クロノバイオロジーはクロノバイオロジーを用います.
- 分子神経科学は分子神経科学である.
- 分子生物学は分子生物学である.
背景:
- シルカディアンリズムは,網膜の光受容体によって太陽の日と同期されます.
- 昼間の時計のフォティックリセットは,SCNにおけるCREB媒介のPer遺伝子誘導を含む.
- シルカディアン・クロック・エントラインメントの正確なメカニズムと遅延は,まだ十分に理解されていない.
研究 の 目的:
- 昼間の時計のリセットの背後にある分子メカニズムを解明する.
- SCNにおける光誘導経路の重要な調節体を特定する.
- 昼間の時計のダイナミクスにおけるSIK1とCRTC1の役割を調査する.
主な方法:
- 上核 (SCN) の光調節トランスクリプトームの分析.
- CRTC1,CREB,SIKの相互作用を調査する1.
- SCNにおけるSik1のノックダウンを使用して,行動的相変化と再訓練を評価する.
主要な成果:
- SIK1とCRTC1は,SCNのクロックリセットにおける重要なコンポーネントとして特定されました.
- 光刺激はCREBのCRTC1共活性化を促進し,Per1とSik1の発現を誘導する.
- SIK1は,CRTC1をリン酸化して無効化することで,システムに負のフィードバックを与え,それによって光の効果を抑制します.
- Sik1のノックダウンは,シミュレートされたジェットラグの後,行動的フェーズシフトを強化し,再トレーニングを加速しました.
結論:
- SIK1はネガティブなフィードバックのレギュレータとして作用し,昼間の時計のリセットに対する光の影響を制限します.
- SIK1-CRTC1-CREB経路は,昼間の引き寄せの速度を決定する重要な決定因子です.
- この経路は,サーカディアンリズム障害の調節のための潜在的な治療目標を表しています.
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