リン酸化は,システィック線維症の呼吸道細胞からの塩化チャネルを活性化することに失敗します

R A Schoumacher¹, R L Shoemaker, D R Halm

¹Department of Pediatrics, University of Alabama, Birmingham 35294.

Nature

|December 24, 1987

まとめ

囊性線維症 (CF) は,呼吸道細胞の塩化物チャネル機能を損なう. 欠陥はチャネルにある.

科学分野:

分子生物学は分子生物学である.
細胞生理学細胞生理学
遺伝性疾患遺伝性疾患は遺伝的に受け継がれる病気です.

背景:

胞性線維症 (Cystic Fibrosis,CF) は,上皮細胞の塩化物浸透性によって特徴づけられる.
頂上膜の塩化物 (Cl-) 経路の異常な調節は,CF呼吸道上皮質の特徴である.
細胞周期性AMP (cAMP) レベルは,CF細胞のアゴニストに反応して通常上昇しますが,チャネル活性化は低下しています.

研究の目的:

性線維症におけるcAMP媒介の塩素チャネル調節における特定の欠陥を調査する.
CF呼吸道上皮細胞の欠陥を局所化するために.
欠陥がタンパク質キナーゼA (PKA) の活性化経路にあるか,下流にあるかを判断する.

主な方法:

正常およびCF呼吸道上皮細胞からの切断された膜パッチを使用しました.
これらのパッチの細胞質表面は,cAMP依存タンパク質キナーゼとATPの触媒子ユニット (C子ユニット) に暴露された.
クロライドチャネル活性が測定され,電気生理学的技術 (電圧誘発活性化およびCサブユニット活性化) を使用して正常およびCF膜を比較しました.

主要な成果:

正常な細胞では,PKAのCサブユニットがCl-チャネルを活性化し,cAMP依存アゴニスト刺激を模倣した.
CF細胞では,CサブユニットはCl-チャネルを活性化することができなかったが,機能的なチャネルは存在していた (電圧誘発活性化によって確認された).
これは,欠陥がPKAの活性化より下流にあることを示します.

結論:

cAMP媒介のクロリドチャネル活性化におけるシスティックフィブロシスの欠陥は,cAMP依存タンパク質キナーゼの活性化から遠隔に位置しています.
この研究は,クロライドチャネルそのものと,それに関連する調節タンパク質が,CFの欠陥の主要な部位であると示唆しています.
この分子欠陥を理解することは,標的型CF治療の開発に不可欠です.

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