miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene
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Authors: | Eric M Hogan Alison P Casserly Michael D Scofield Zhongming Mou Rubing Zhao-Shea Chris W Johnson Andrew R Tapper Paul D Gardner |
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Institution: | 1.Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA;2.Interdisciplinary Graduate Program, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA;3.UMMS MD/PhD Program, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA |
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Abstract: | Nicotine binds to and activates a family of ligand-gated ion channels, neuronal nicotinic
acetylcholine receptors (nAChRs). Chronic nicotine exposure alters the expression of various nAChR
subtypes, which likely contributes to nicotine dependence; however, the underlying mechanisms
regulating these changes remain unclear. A growing body of evidence indicates that microRNAs
(miRNAs) may be involved in nAChR regulation. Using bioinformatics, miRNA library screening,
site-directed mutagenesis, and gene expression analysis, we have identified a limited number of
miRNAs that functionally interact with the 3′-untranslated regions (3′ UTRs) of
mammalian neuronal nAChR subunit genes. In silico analyses revealed specific, evolutionarily
conserved sites within the 3′ UTRs through which the miRNAs regulate gene expression.
Mutating these sites disrupted miRNA regulation confirming the in silico predictions. In addition,
the miRNAs that target nAChR 3′ UTRs are expressed in mouse brain and are regulated by
chronic nicotine exposure. Furthermore, we show that expression of one of these miRNAs, miR-542-3p,
is modulated by nicotine within the mesocorticolimbic reward pathway. Importantly, overexpression of
miR-542-3p led to a decrease in the protein levels of its target, the nAChR β2 subunit.
Bioinformatic analysis suggests that a number of the miRNAs play a general role in regulating
cholinergic signaling. Our results provide evidence for a novel mode of nicotine-mediated regulation
of the mammalian nAChR gene family. |
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Keywords: | nicotinic acetylcholine receptor miRNA analysis gene expression miR-542-3p |
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