Man overboard! Rescuing myocardium with membrane rafts.
Man overboard! Rescuing myocardium with membrane rafts.
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有人落水！
DOI：
10.1097/aln.0b013e3181d3d812
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发表时间：
2010
期刊：
影响因子：
8.8
通讯作者：
Kersten,JudyR
中科院分区：
文献类型：
--
作者：
Lohr,Nicole;Kersten,JudyR
挥发性麻醉剂通过刺激一系列细胞内信号传导事件产生重要的心脏保护作用，最终使心肌抵抗梗死。众所周知，麻醉剂可以暂时保护心脏。暴露于异氟烷或其他挥发性药物后，最初的早期心肌保护窗口持续数小时，24至48小时后再次出现心肌保护。早期和延迟麻醉预适应的机制不同。麻醉剂激活各种细胞内激酶，这些激酶磷酸化并随后改变下游蛋白质（例如内皮型一氧化氮合酶[eNOS]和三磷酸腺苷调节的钾通道）的活性，这些蛋白质在介导心脏保护中很重要。在早期预处理阶段，预先存在的蛋白质的修饰导致保护，而24小时后，心脏保护依赖于新蛋白质的合成。这些信号转导事件的复杂性需要功能和空间组织，以及大量细胞内蛋白质活性的协调。在本期杂志中，Tsutsumi等人1证明异氟烷通过调节膜（脂）筏中发现的一种关键蛋白质小窝蛋白-3对心肌梗死产生延迟保护作用（图1）.作为质膜经典流体脂质双层模型的延伸，脂质/膜筏很小，在一个实施方案中，微结构域（10-200 nm）富含甾醇、鞘脂和胆固醇，“漂浮”在磷脂的海洋中。2这些脂质结构域形成对接平台，控制细胞内信号转导事件的位置。筏位于质膜上，也存在于内质网和线粒体中。膜筏的功能是通过将蛋白质浓缩到高度特异性的细胞内位置来调节细胞过程。脂筏的形成是高度动态的，这种性质允许蛋白质信号传导和运输的时间调节。膜筏的一个亚类是小窝，其是细胞膜（60-80 nm）的烧瓶样内陷，其特征在于存在支架蛋白小窝蛋白-1、-2和-3。Caveolin-1和Caveolin-2在脂肪细胞、内皮细胞和成纤维细胞中高度表达，而Caveolin-3主要在骨骼肌、心脏和平滑肌细胞中表达。小窝在小窝蛋白-1和小窝蛋白-3敲除小鼠中被破坏，但在小窝蛋白-2突变体中被保留。Caveolins通过一个特定的结构域与蛋白质结合，使蛋白质发生构象变化，并调节信号转导分子的活性。小窝蛋白是小窝形成所必需的，它们的表达间接调节可用于功能性信号转导的小窝的数量。窖蛋白可以改变
Volatile anesthetics produce important cardioprotective effects by stimulating a series of intracellular signaling events that ultimately render myocardium resistant to infarction. Anesthetics are known to protect the heart in a temporal manner. An initial early window of myocardial protection lasts hours after exposure to isoflurane or other volatile agents, and myocardial protection reappears again 24 to 48 h later. The mechanisms of early and delayed anesthetic preconditioning differ. Anesthetics activate various intracellular kinases which phosphorylate and subsequently modify the activity of downstream proteins (eg, endothelial nitric oxide synthase [eNOS] and adenosine triphosphate-regulated potassium channels) that are important in mediating cardioprotection. During the early preconditioning phase, modification of preexisting proteins leads to protection, whereas after 24 h, cardioprotection relies on the synthesis of new proteins. The complexity of these signal transduction events requires both functional and spatial organization, and coordination of the activity of a large number of intracellular proteins. In this issue of the Journal, Tsutsumi et al1 demonstrate that isoflurane produces delayed protection against myocardial infarction by modulating a key protein, caveolin-3, found in membrane (lipid) rafts (fig. 1).An extension of the classical fluid lipid bilayer model of the plasma membrane, lipid/membrane rafts are small (10–200 nm) microdomains enriched in sterols, sphingolipids and cholesterol “floating” in a sea of phospholipids. 2 These lipid domains form docking platforms that control the location of intracellular signal transduction events. Rafts are located in the plasma membrane, and are also found in the endoplasmic reticulum and mitochondria. Membrane rafts function to regulate cellular processes by concentrating proteins to highly specific intracellular locations. The formation of lipid rafts is highly dynamic and this property allows for temporal regulation of protein signaling and trafficking. A subclass of membrane rafts are the caveolae, which are flask-like invaginations of the cellular membrane (60–80 nm), distinguished by the presence of scaffolding proteins caveolin-1,-2, and-3. 3 Caveolins-1 and-2 are highly expressed in adipocytes, endothelial cells, and fibroblasts, whereas, caveolin-3 is expressed predominantly in skeletal, cardiac, and smooth muscle cells. Caveolae are disrupted in caveolin-1 and caveolin-3 knock out mice, but are preserved in caveolin-2 mutants. 4 Caveolins bind proteins through a specific domain that enables conformational changes to occur and this action regulates the activity of signal transduction molecules. Caveolins are required for caveolae formation and their expression indirectly regulates the number of caveolae available for functional signal transduction. Caveolins can alter the fluidity of