A Major Species of Mouse μ-opioid Receptor mRNA and Its Promoter-Dependent Functional Polyadenylation Signal

Wu, Qiming; Hwang, Cheol Kyu; Yao, Shiyi; Law, Ping Yee; Loh, Horace H.; Wei, Li‐Na

doi:10.1124/mol.105.012567

Cited by 16 publications

(21 citation statements)

References 28 publications

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“…Such regulation could be due to mRNA stability, differences in translation efficiency or mRNA transport, and covalent modification of receptor molecules (10,12–14). Our recent studies indicated that the 3′-untranslated region (UTR) of MOR mRNA could affect the overall transcript's activity (15). Thus, posttranscriptional regulation of the MOR gene could have an important role in the spatial and temporal expression of the receptor proteins.…”

Section: Introductionmentioning

confidence: 99%

Translational repression of mouse mu opioid receptor expression via leaky scanning

Song

Hwang

Kim

et al. 2007

Nucleic Acids Research

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Mu opioid receptor (MOR) expression is under temporal and spatial controls, but expression levels of the MOR gene are relatively low in vivo. In addition to transcriptional regulations, upstream AUGs (uAUGs) and open reading frames (uORFs) profoundly affect the translation of the primary ORF and thus the protein levels in several genes. The 5′-untranslated region (UTR) of mouse MOR mRNA contains three uORFs preceding the MOR main initiation codon. In MOR-fused EGFP or MOR promoter/luciferase reporter constructs, mutating each uAUG individually or in combinations increased MOR transient heterologous expression in neuroblastoma NMB and HEK293 cells significantly. Translation of such constructs increased up to 3-fold without altering the mRNA levels if either the third uAUG or both the second and third AUGs were mutated. Additionally, these uAUG-mediated translational inhibitions were independent of their peptide as confirmed by internal mutation analyses in each uORF. Translational studies indicated that protein syntheses were initiated at these uAUG initiation sites, with the third uAUG initiating the highest translation level. These results support the hypothesis that uORFs in mouse MOR mRNA act as negative regulators through a ribosome leaky scanning mechanism. Such leaky scanning resulted in the suppression of mouse MOR under normal conditions.

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Section: Introductionmentioning

confidence: 99%

Translational repression of mouse mu opioid receptor expression via leaky scanning

Song

Hwang

Kim

et al. 2007

Nucleic Acids Research

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“…Most of the mRNA corresponds to UTR because the coding region of MOR-1 covers only Mu Opioids and Their Receptors: Evolution of a Concept ;1.2 kb. In both mouse and human transcripts, exon 4 contains a poly(A) site and is expressed as a 10-to 13-kb exon Wu et al, 2005). Northern blot analysis also reveals several smaller bands dependent upon the probes used in the mouse (Pan et al, 2001), rat , and human brains (Pan et al, 2003;Raynor et al, 1995), raising the possibility of alternative splicing.…”

Section: E Regional Expression Of Mor-1 In the Centralmentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

Pasternak

Pan

2013

Pharmacological Reviews

494

526

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“…The complete 39-UTR containing polyadenylation [poly(A)] signal and cleavage site of the original human and mouse MOR-1 was identified (Ide et al, 2005;Wu et al, 2005). However, little is known for the 39-UTR of the OPRM1 splice variants including MOR-1A.…”

Section: Introductionmentioning

confidence: 99%

Morphine Regulates Expression of μ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of the μ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

et al. 2014

Molecular Pharmacology

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The m-opioid receptor (MOR-1) gene OPRM1 undergoes extensive alternative splicing, generating an array of splice variants. Of these variants, MOR-1A, an intron-retention carboxyl terminal splice variant identical to MOR-1 except for the terminal intracellular tail encoded by exon 3b, is quite abundant and conserved from rodent to humans. Increasing evidence indicates that miroRNAs (miRNAs) regulate MOR-1 expression and that m agonists such as morphine modulate miRNA expression. However, little is known about miRNA regulation of the OPRM1 splice variants. Using 39-rapid amplification cDNA end and Northern blot analyses, we identified the complete 39-untranslated region (39-UTR) for both mouse and human MOR-1A and their conserved polyadenylation site, and defined the role the 39-UTR in mRNA stability using a luciferase reporter assay. Computer models predicted a conserved miR-103/107 targeting site in the 39-UTR of both mouse and human MOR-1A. The functional relevance of miR-103/107 in regulating expression of MOR-1A protein through the consensus miR-103/107 binding sites in the 39-UTR was established by using mutagenesis and a miR-107 inhibitor in transfected human embryonic kidney 293 cells and Be (2)C cells that endogenously express human MOR-1A. Chronic morphine treatment significantly upregulated miR-103 and miR-107 levels, leading to downregulation of polyribosome-associated MOR-1A in both Be(2)C cells and the striatum of a morphinetolerant mouse, providing a new perspective on understanding the roles of miRNAs and OPRM1 splice variants in modulating the complex actions of morphine in animals and humans.

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A Major Species of Mouse μ-opioid Receptor mRNA and Its Promoter-Dependent Functional Polyadenylation Signal

Abstract: The pharmacological effects of opioid drugs are mediated mainly by the -opioid receptor (MOR

Cited by 16 publications

References 28 publications

Translational repression of mouse mu opioid receptor expression via leaky scanning

Translational repression of mouse mu opioid receptor expression via leaky scanning

Mu Opioids and Their Receptors: Evolution of a Concept

Morphine Regulates Expression of μ-Opioid Receptor MOR-1A, an Intron-Retention Carboxyl Terminal Splice Variant of the μ-Opioid Receptor (OPRM1) Gene via miR-103/miR-107

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