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MiRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family.

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 ?2 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.

SUBMITTER: Hogan EM

PROVIDER: S-EPMC4238110 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family.

Hogan Eric M EM Casserly Alison P AP Scofield Michael D MD Mou Zhongming Z Zhao-Shea Rubing R Johnson Chris W CW Tapper Andrew R AR Gardner Paul D PD

RNA (New York, N.Y.) 20141024 12

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 ...[more]

PMID: 25344397

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Project description:BackgroundNicotinic acetylcholine receptors (nAChRs) mediate fast synaptic cholinergic transmission in the insect central nervous system. The insect nAChR is the molecular target of a class of insecticides, neonicotinoids. Like mammalian nAChRs, insect nAChRs are considered to be made up of five subunits, coded by homologous genes belonging to the same family. The nAChR subunit genes of Drosophila melanogaster, Apis mellifera and Anopheles gambiae have been cloned previously based on their genome sequences. The silkworm Bombyx mori is a model insect of Lepidoptera, among which are many agricultural pests. Identification and characterization of B. mori nAChR genes could provide valuable basic information for this important family of receptor genes and for the study of the molecular mechanisms of neonicotinoid action and resistance.ResultsWe searched the genome sequence database of B. mori with the fruit fly and honeybee nAChRs by tBlastn and cloned all putative silkworm nAChR cDNAs by reverse transcriptase-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) methods. B. mori appears to have the largest known insect nAChR gene family to date, including nine alpha-type subunits and three beta-type subunits. The silkworm possesses three genes having low identity with others, including one alpha and two beta subunits, alpha 9, beta2 and beta 3. Like the fruit fly and honeybee counterparts, silkworm nAChR gene alpha 6 has RNA-editing sites, and alpha 4, alpha 6 and alpha 8 undergo alternative splicing. In particular, alternative exon 7 of Bm alpha 8 may have arisen from a recent duplication event. Truncated transcripts were found for Bm alpha 4 and Bm alpha 5.ConclusionB. mori possesses a largest known insect nAChR gene family characterized to date, including nine alpha-type subunits and three beta-type subunits. RNA-editing, alternative splicing and truncated transcripts were found in several subunit genes, which might enhance the diversity of the gene family.

Dataset Information

MiRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family.

Publications

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family.

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