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首页> 外文期刊>Neuron >Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol.
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Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol.

机译：miR-9对BK通道剪接变体稳定性的转录后调节是对酒精神经适应的基础。

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摘要

Tolerance represents a critical component of addiction. The large-conductance calcium- and voltage-activated potassium channel (BK) is a well-established alcohol target, and an important element in behavioral and molecular alcohol tolerance. We tested whether microRNA, a newly discovered class of gene expression regulators, plays a role in the development of tolerance. We show that in adult mammalian brain, alcohol upregulates microRNA miR-9 and mediates posttranscriptional reorganization in BK mRNA splice variants by miR-9-dependent destabilization of BK mRNAs containing 3'UTRs with a miR-9 Recognition Element (MRE). Different splice variants encode BK isoforms with different alcohol sensitivities. Computational modeling indicates that this miR-9-dependent mechanism contributes to alcohol tolerance. Moreover, this mechanism can be extended to include regulation of additional miR-9 targets relevant to alcohol abuse. Our results describe a mechanism of multiplex regulation of stability of alternatively spliced mRNA by microRNA in drug adaptation and neuronal plasticity.
机译：宽容是成瘾的重要组成部分。大电导钙和电压激活的钾通道（BK）是公认的酒精靶标，并且是行为和分子酒精耐受性的重要元素。我们测试了microRNA（一种新发现的基因表达调节剂）是否在耐受性的发展中起作用。我们显示，在成年哺乳动物的大脑中，酒精上调miRNA miR-9并通过miR-9依赖的含有3'UTR和miR-9识别元件（MRE）的BK mRNA的miR-9依赖性去稳定化介导BK mRNA剪接变体中的转录后重组。不同的剪接变体编码具有不同醇敏感性的BK同工型。计算模型表明，这种miR-9依赖性机制有助于提高酒精耐受性。此外，该机制可以扩展为包括对与酗酒有关的其他miR-9靶标的调控。我们的结果描述了在药物适应性和神经元可塑性中通过microRNA交替剪接的mRNA稳定性的多重调控机制。

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