Acute alcohol action and desensitization of ligand-gated ion channels.
Acute alcohol action and desensitization of ligand-gated ion channels.
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DOI：
10.1124/pr.108.000430
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发表时间：
2009-03
影响因子：
21.1
通讯作者：
Lovinger DM
中科院分区：
文献类型：
--
作者：
Dopico AM;Lovinger DM
乙醇通过多种受体发挥其生物学作用，包括离子通道。离子通道是敏感的相关乙醇浓度构成了一个异质集，包括结构无关的蛋白质只共享的属性，其门控是由一个或多个配体调节。在这些通道中，受体脱敏几乎是普遍的，并且其由乙醇的调节可能是酒精药理学和体内效应的关键方面。我们回顾了乙醇和离子型受体脱敏之间相互作用的证据，以及这种相互作用对乙醇对通道功能的整体作用的贡献。在某些情况下，如3型5-羟色胺、烟碱乙酰胆碱、GABA-A和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯受体，乙醇对表观脱敏的作用在药物对受体功能的急性作用中起重要作用。在少数情况下，诱变有助于识别受体蛋白中不同的区域，这些区域差异地感知正醇，从而导致受体脱敏的差异调节。然而，受体的脱敏与多种可能改变蛋白质构象的生化过程有关，如脂质微环境、翻译后通道修饰和通道亚基组成，这些过程对乙醇与通道脱敏相互作用的相对贡献仍不清楚。了解乙醇和离子型受体脱敏之间的相互作用可能有助于解释不同的乙醇行动1）当乙醇在体外评估克隆的通道蛋白，2）在生理或病理条件下，或在不同的细胞结构域与修改配体浓度和/或受体构象。最后，受体脱敏可能参与对乙醇的分子耐受性，也可能参与对乙醇的行为耐受性，这被认为是导致酒精中毒风险的原因。
Ethanol exerts its biological actions through multiple receptors, including ion channels. Ion channels that are sensitive to pharmacologically relevant ethanol concentrations constitute a heterogeneous set, including structurally unrelated proteins solely sharing the property that their gating is regulated by a ligand(s). Receptor desensitization is almost universal among these channels, and its modulation by ethanol may be a crucial aspect of alcohol pharmacology and effects in the body. We review the evidence documenting interactions between ethanol and ionotropic receptor desensitization, and the contribution of this interaction to overall ethanol action on channel function. In some cases, such as type 3 serotonin, nicotinic acetylcholine, GABA-A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, ethanol actions on apparent desensitization play a significant role in acute drug action on receptor function. In a few cases, mutagenesis helped to identify different areas within a receptor protein that differentially sense n-alcohols, resulting in differential modulation of receptor desensitization. However, desensitization of a receptor is linked to a variety of biochemical processes that may alter protein conformation, such as the lipid microenvironment, post-translational channel modification, and channel subunit composition, the relative contribution of these processes to ethanol interactions with channel desensitization remains unclear. Understanding interactions between ethanol and ionotropic receptor desensitization may help to explain different ethanol actions 1) when ethanol is evaluated in vitro on cloned channel proteins, 2) under physiological or pathological conditions or in distinct cell domains with modified ligand concentration and/or receptor conformation. Finally, receptor desensitization is likely to participate in molecular and, possibly, behavioral tolerance to ethanol, which is thought to contribute to the risk of alcoholism.
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影响因子：
2.3
作者：
Botta, Paolo;Radcliffe, Richard A.;Valenzuela, C. Fernando
通讯作者：
Valenzuela, C. Fernando
影响因子：
--
作者：
Brody, Arthur L.;Mandelkern, Mark A.;Mukhin, Alexey G.
通讯作者：
Mukhin, Alexey G.
影响因子：
7.3
作者：
Akinshola, BE
通讯作者：
Akinshola, BE
影响因子：
3.6
作者：
Akk, Gustav;Li, Ping;Steinbach, Joe Henry
通讯作者：
Steinbach, Joe Henry
影响因子：
--
作者：
Barrantes, FJ
通讯作者：
Barrantes, FJ