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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Potent block of Cx36 and Cx50 gap junction channels by mefloquine
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Potent block of Cx36 and Cx50 gap junction channels by mefloquine

机译：甲氟喹对Cx36和Cx50间隙连接通道的有效阻滞

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摘要

Recently, great interest has been shown in understanding the functional roles of specific gap junction proteins (connexins) in brain, lens, retina, and elsewhere. Some progress has been made by studying knockout mice with targeted connexin deletions. For example, such studies have implicated the gap junction protein Cx36 in synchronizing rhythmic activity of neurons in several brain regions. Although knockout strategies are informative, they can be problematic, because compensatory changes sometimes occur during development. Therefore, it would be extremely useful to have pharmacological agents that block specific connexins, without major effects on other gap junctions or membrane channels. We show that mefloquine, an antimalarial drug, is one such agent. It blocked Cx36 channels, expressed in transfected N2A neuroblastoma cells, at low concentrations (IC50 approximate to 300 nM). Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC50 approximate to 1.1 muM). However, other gap junctions (e.g., Cx43, Cx32, and Cx26) were only affected at concentrations 10- to 100-fold higher. To further examine the utility and specificity of this compound, we characterized its effects in acute brain slices. Mefloquine, at 25 muM, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions. At this concentration, the only major side effect was an increase in spontaneous synaptic activity. Mefloquine (25 muM) caused no significant change in evoked excitatory or inhibitory postsynaptic potentials, and intrinsic cellular properties were also mostly unaffected. Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50.
机译：最近，人们对了解特定的间隙连接蛋白（连接蛋白）在脑，晶状体，视网膜和其他部位的功能作用表现出极大的兴趣。通过研究具有针对性的连接蛋白缺失的基因敲除小鼠已经取得了一些进展。例如，此类研究表明间隙连接蛋白Cx36可以同步多个大脑区域的神经元的节律活动。尽管基因剔除策略是有益的，但它们可能会带来问题，因为在开发过程中有时会发生补偿性变化。因此，拥有能阻断特定连接蛋白而不对其他间隙连接或膜通道产生重大影响的药理剂将极为有用。我们表明甲氟喹是一种抗疟疾药物，是一种这样的药物。它以低浓度（IC50约为300 nM）阻断了在转染的N2A神经母细胞瘤细胞中表达的Cx36通道。美洛喹还阻断了由晶状体间隙连接蛋白Cx50（IC50约1.1μM）形成的通道。但是，其他间隙连接（例如Cx43，Cx32和Cx26）仅在浓度高10至100倍时受到影响。为了进一步检查该化合物的效用和特异性，我们表征了其在急性脑切片中的作用。 25μM的甲氟喹以最小的非特异性作用阻断了新皮层切片中神经元之间的间隙连接偶联。在此浓度下，唯一的主要副作用是自发突触活性的增加。甲氟喹（25μM）不会引起诱发的兴奋性或抑制性突触后电位的显着变化，并且固有的细胞特性也大多不受影响。因此，甲氟喹有望成为研究Cx36和Cx50的功能角色的有用工具。

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