Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses.
Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses.
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DOI：
10.1016/j.phrs.2015.07.002
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发表时间：
2015-11
影响因子：
9.3
通讯作者：
Aguayo LG
中科院分区：
文献类型：
--
作者：
Burgos CF;Muñoz B;Guzman L;Aguayo LG
人们普遍认为，滥用乙醇会造成严重的健康和经济问题。由于其令人陶醉和上瘾的特性，有必要分析其对中枢神经系统的影响。然而，我们现在才了解到控制乙醇修饰重要膜蛋白（如配体激活离子通道）的机制。此外，直到最近，人们才将这些影响与行为改变联系起来。目前的研究表明，甘氨酸受体（GlyR）是低浓度乙醇（5至100 mM）的易感靶点。GlyRs与乙醇的作用有关，因为它们在脊髓和脑干中被发现，它们主要表达α1亚基。最近，GlyRs的存在被描述为存在于更高的区域，如海马和伏隔核，普遍存在α2/α3亚基。本文综述了乙醇对GlyRs的影响：1)乙醇与细胞外或跨膜结构域氨基酸的直接相互作用，以及通过激活信号转导途径的间接机制；2)分析对乙醇具有不同敏感性的α2和α3亚基，从而确定存在于细胞内结构域和c端区域的乙醇调节的结构要求；3) α1 GlyRs基因敲入小鼠与G蛋白的相互作用受损，乙醇敏感性降低，但甘氨酸能传递没有改变；4) GlyRs作为潜在的治疗靶点。
It is well accepted that ethanol is able to produce major health and economic problems associated to its abuse. Because of its intoxicating and addictive properties, it is necessary to analyze its effect in the central nervous system. However, we are only now learning about the mechanisms controlling the modification of important membrane proteins such as ligand-activated ion channels by ethanol. Furthermore, only recently are these effects being correlated to behavioral changes. Current studies show that the glycine receptor (GlyR) is a susceptible target for low concentrations of ethanol (5 to 100 mM). GlyRs are relevant for the effects of ethanol because they are found in the spinal cord and brain stem where they primarily express the α1 subunit. More recently, the presence of GlyRs was described in higher regions, such as the hippocampus and nucleus accumbens, with a prevalence of α2/α3 subunits. Here, we review data on the following aspects of ethanol effects on GlyRs: 1) direct interaction of ethanol with amino acids in the extracellular or transmembrane domains, and indirect mechanisms through the activation of signal transduction pathways; 2) analysis of α2 and α3 subunits having different sensitivities to ethanol which allows the identification of structural requirements for ethanol modulation present in the intracellular domain and C-terminal region; 3) Genetically modified knock-in mice for α1 GlyRs that have an impaired interaction with G protein and demonstrate reduced ethanol sensitivity without changes in glycinergic transmission; and 4) GlyRs as potential therapeutic targets.