Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Graduate School of Biomedical Sciences, MD/PhD Program; Graduate School of Biomedical Sciences, Interdisciplinary Graduate Program; Tapper Lab; Gardner Lab
Neuroscience and Neurobiology
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 beta2 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.
gene expression, miR-542-3p, miRNA analysis, nicotinic acetylcholine receptor
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© 2014 Hogan et al. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
DOI of Published Version
RNA. 2014 Dec;20(12):1890-9. doi: 10.1261/rna.034066.112. Epub 2014 Oct 24. Link to article on publisher's site
RNA (New York, N.Y.)
Hogan, Eric M.; Casserly, Alison P.; Scofield, Michael D.; Mou, Zhongming; Zhao-Shea, Rubing; Johnson, Chris W.; Tapper, Andrew R.; and Gardner, Paul D., "miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family" (2014). University of Massachusetts Medical School Faculty Publications. 1468.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License