异丙酚诱导活细胞蛋白激酶 C (PKC) 易位和激活的特征和机制,Frontiers in Pharmacology

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异丙酚诱导活细胞蛋白激酶 C (PKC) 易位和激活的特征和机制
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2023-11-07 , DOI: 10.3389/fphar.2023.1284586
Soma Noguchi ₁ , Taketoshi Kajimoto ₂ , Takuya Kumamoto ₃ , Masashi Shingai ₁ , Soshi Narasaki _{1,

4} , Tomoaki Urabe _{1,

4} , Serika Imamura ₅ , Kana Harada ₁ , Izumi Hide ₁ , Sigeru Tanaka ₁ , Yuhki Yanase ₆ , Shun-Ichi Nakamura ₂ , Yasuo M Tsutsumi ₄ , Norio Sakai ₁

Affiliation

背景和目的：本研究旨在阐明丙泊酚的作用机制，特别是丙泊酚诱导的蛋白激酶C（PKC）易位的作用机制。实验方法：各种PKC与绿色荧光蛋白（PKC-GFP）或其他GFP融合融合蛋白在 HeLa 细胞中表达，并使用共焦激光扫描显微镜观察其异丙酚诱导的动力学。使用 C 激酶活性受体 (CKAR)（细胞内 PKC 激活的指标）来评估异丙酚诱导的细胞 PKC 激活。我们还使用异丙酚的异构体和衍生物检查了 PKC 易位，以确定该过程中涉及的关键结构基序。主要结果：异丙酚持续将 PKCα 常规 PKC 和 PKCδ 从新型 PKC (nPKC) 易位到质膜 (PM)。异丙酚将 nPKC 的 PKCδ 和 PKCη 分别转移至高尔基体和内质网。异丙酚还能诱导非典型PKC或PKC以外的蛋白质的PKCδ发生核转位，使核内外的蛋白质浓度变得均匀。CKAR 分析显示，异丙酚激活 PM 和高尔基体中的 PKC。此外，使用异丙酚异构体和衍生物的测试预测，对于诱导PKC和核转位重要的结构基序是不同的。结论和意义：异丙酚诱导PKCs的亚型特异性细胞内转位并激活PKCs。此外，异丙酚可能通过改变核膜的通透性来诱导 PKC 和其他蛋白质的核易位。有趣的是，异丙酚诱导的 PKC 和核转位可能通过不同的机制发生。我们的研究结果提供了对异丙酚作用机制的见解。

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Features and mechanisms of propofol-induced protein kinase C (PKC) translocation and activation in living cells

Background and purpose: In this study, we aimed to elucidate the action mechanisms of propofol, particularly those underlying propofol-induced protein kinase C (PKC) translocation.Experimental approach: Various PKCs fused with green fluorescent protein (PKC-GFP) or other GFP-fused proteins were expressed in HeLa cells, and their propofol-induced dynamics were observed using confocal laser scanning microscopy. Propofol-induced PKC activation in cells was estimated using the C kinase activity receptor (CKAR), an indicator of intracellular PKC activation. We also examined PKC translocation using isomers and derivatives of propofol to identify the crucial structural motifs involved in this process.Key results: Propofol persistently translocated PKCα conventional PKCs and PKCδ from novel PKCs (nPKCs) to the plasma membrane (PM). Propofol translocated PKCδ and PKCη of nPKCs to the Golgi apparatus and endoplasmic reticulum, respectively. Propofol also induced the nuclear translocation of PKCζ of atypical PKCs or proteins other than PKCs, such that the protein concentration inside and outside the nucleus became uniform. CKAR analysis revealed that propofol activated PKC in the PM and Golgi apparatus. Moreover, tests using isomers and derivatives of propofol predicted that the structural motifs important for the induction of PKC and nuclear translocation are different.Conclusion and implications: Propofol induced the subtype-specific intracellular translocation of PKCs and activated PKCs. Additionally, propofol induced the nuclear translocation of PKCs and other proteins, probably by altering the permeability of the nuclear envelope. Interestingly, propofol-induced PKC and nuclear translocation may occur via different mechanisms. Our findings provide insights into the action mechanisms of propofol.

更新日期：2023-11-07

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