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Membrane-Mediated Activity of Local Anesthetics
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2021-11-01 , DOI: 10.1124/molpharm.121.000252
Stephan L Grage 1 , Anke Culetto 1 , Anne S Ulrich 1 , Stefan Weinschenk 2
Affiliation  

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs’ amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics.

中文翻译:

局部麻醉剂的膜介导活性

局部麻醉剂 (LA) 的活性归因于离子通道的抑制,从而导致麻醉。然而,越来越多的研究表明 LA 作用于广泛的受体和通道蛋白,远远超出简单的镇痛作用。当前的配体识别概念可能无法解释受 LA 影响的众多蛋白质靶点。我们假设 LA 可以在不直接结合受体蛋白的情况下引起麻醉,仅通过基于 LA 的两亲性改变围绕这些蛋白质和离子通道的脂质双层的物理特性。LA 可能以下列方式之一起作用:它们 1) 溶解筏状膜微区,2) 通过降低脂质相变温度来阻碍神经冲动传播,或 3) 调节脂质双层的侧向压力分布。这也可以解释除麻醉外 LA 的许多其他作用。此外,膜介导的活性和与离子通道结合的概念不必相互排斥。如果我们将 LA 视为一端非特异性膜介导活性和另一端高度特异性配体结合之间连续体的中间部分,我们可以将 LA 描述为全身麻醉剂和毒素的非特异性作用与其高度特异性的受体结合。这种全面的膜介导模型为局部麻醉剂的临床和药物研究以及治疗应用提供了新的视角。膜介导的活性和与离子通道结合的概念不必相互排斥。如果我们将 LA 视为一端非特异性膜介导活性和另一端高度特异性配体结合之间连续体的中间部分,我们可以将 LA 描述为全身麻醉剂和毒素的非特异性作用与其高度特异性的受体结合。这种全面的膜介导模型为局部麻醉剂的临床和药物研究以及治疗应用提供了新的视角。膜介导的活性和与离子通道结合的概念不必相互排斥。如果我们将 LA 视为一端非特异性膜介导活性和另一端高度特异性配体结合之间连续体的中间部分,我们可以将 LA 描述为全身麻醉剂和毒素的非特异性作用与其高度特异性的受体结合。这种全面的膜介导模型为局部麻醉剂的临床和药物研究以及治疗应用提供了新的视角。我们可以将 LA 描述为全身麻醉药和毒素的非特异性作用与其高度特异性受体结合之间的联系。这种全面的膜介导模型为局部麻醉剂的临床和药物研究以及治疗应用提供了新的视角。我们可以将 LA 描述为全身麻醉药和毒素的非特异性作用与其高度特异性受体结合之间的联系。这种全面的膜介导模型为局部麻醉剂的临床和药物研究以及治疗应用提供了新的视角。
更新日期:2021-10-22
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