MicroRNA 142-3p mediates post-transcriptional regulation of D1 dopamine receptor expression.
MicroRNA 142-3p mediates post-transcriptional regulation of D1 dopamine receptor expression.
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DOI：
10.1371/journal.pone.0049288
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kuzhikandathil EV
中科院分区：
文献类型：
--
作者：
Tobón KE;Chang D;Kuzhikandathil EV
D1多巴胺受体亚型在脑、肾和淋巴细胞中表达。D1受体的功能已被广泛研究，该受体已被证明可调节广泛的生理功能和行为。已知D1受体的表达在发育、疾病状态和慢性治疗过程中发生变化;然而，在这些情况下介导D1受体表达变化的分子机制尚不清楚。虽然以前的研究已经确定了调节D1受体基因转录的细胞外因子和信号传导机制，但对调节D1受体基因表达的其他调节机制知之甚少。在这里，我们报告说，D1受体是转录后调节在出生后小鼠大脑发育和小鼠CAD儿茶酚胺能神经元细胞系。我们证明，这种转录后调控是由一个分子机制，涉及非编码RNA介导的。结果表明，D1受体mRNA的3′端非翻译区（1277 bp）是介导转录后调控的必要和充分的区域。利用缺失和定点突变的方法，我们发现D1受体的转录后调控是由microRNA miR-142- 3 p与D1受体mRNA 3′端非翻译区1277 bp的一个共有结合位点相互作用而特异性介导的。抑制CAD细胞中的内源性miR-142- 3 p增加了内源性D1受体蛋白表达水平。D1受体蛋白水平的增加具有生物学意义，因为它导致增强的D1受体介导的信号传导，通过测量腺苷酸环化酶和多巴胺和cAMP调节的磷蛋白DARPP-32的活化来确定。我们还发现，在出生后发育过程中，小鼠大脑中miR-142- 3 p水平和D1受体蛋白表达之间存在负相关。这是第一个研究证明D1受体表达的转录后调节是由microRNA诱导的翻译抑制介导的。
The D1 dopamine receptor subtype is expressed in the brain, kidney and lymphocytes. D1 receptor function has been extensively studied and the receptor has been shown to modulate a wide range of physiological functions and behaviors. The expression of D1 receptor is known to change during development, disease states and chronic treatment; however, the molecular mechanisms that mediate the changes in D1 receptor expression under these circumstances are not well understood. While previous studies have identified extracellular factors and signaling mechanisms regulating the transcription of D1 receptor gene, very little is known about other regulatory mechanisms that modulate the expression of the D1 receptor gene. Here we report that the D1 receptor is post-transcriptionally regulated during postnatal mouse brain development and in the mouse CAD catecholaminergic neuronal cell line. We demonstrate that this post-transcriptional regulation is mediated by a molecular mechanism involving noncoding RNA. We show that the 1277 bp 3′untranslated region of D1 receptor mRNA is necessary and sufficient for mediating the post-transcriptional regulation. Using deletion and site-directed mutagenesis approaches, we show that the D1 receptor post-transcriptional regulation is specifically mediated by microRNA miR-142-3p interacting with a single consensus binding site in the 1277 bp 3′untranslated region of D1 receptor mRNA. Inhibiting endogenous miR-142-3p in CAD cells increased endogenous D1 receptor protein expression levels. The increase in D1 receptor protein levels was biologically significant as it resulted in enhanced D1 receptor-mediated signaling, determined by measuring the activation of both, adenylate cyclase and, the dopamine- and cAMP-regulated phosphoprotein, DARPP-32. We also show that there is an inverse correlation between miR-142-3p levels and D1 receptor protein expression in the mouse brain during postnatal development. This is the first study to demonstrate that the post-transcriptional regulation of D1 receptor expression is mediated by microRNA-induced translational suppression.
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