Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the
            <i>Oprm</i>
            gene

Pan, Ying‐Xian; Xu, Jin; Mahurter, Loriann; Bolan, Elizabeth; Xu, Mingming; Pasternak, Gavril W.

doi:10.1073/pnas.241296098

Cited by 173 publications

(199 citation statements)

References 28 publications

Supporting

Mentioning

192

Contrasting

Order By: Relevance

“…Early studies established the existence of 3Ј-splicing, with a series of exon 1 variants differing only in their amino acid sequence at the tip of the intracellular C terminus. A second set of 5Ј splice variants associated with exon 11, located about 30 kb upstream of exon 1 and under the control of a physically distinct promoter, illustrates the complex nature of this gene (8). The current study establishes both the expression and relevance of the exon 11-associated splice variants.…”

Section: Discussionsupporting

confidence: 54%

“…1) (8) and, most recently, in humans (22). These variants are associated with exon 11, which is located Ϸ30 kb upstream of exon 1 in the mouse and is under the control of its own exon 11 promoter (8,23). This possibility was supported by the observation that exon 1 knockout animals that still responded to heroin continued to express mRNA transcripts from the MOR-1 gene (19).…”

mentioning

confidence: 99%

“…This inability to reconcile the diverse pharmacology of -opioids with their binding selectivity led to the proposal of multiple -opioid-receptors (7), a concept initially proposed based on binding and pharmacological studies in animal models and subsequently confirmed with the identification of a large number of splice variants of the cloned -opioid-receptor MOR-1 in mice, rats, and humans ( Fig. 1A) (8)(9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

Pan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

100

140

View full text Add to dashboard Cite

Heroin remains a major drug of abuse and is preferred by addicts over morphine. Like morphine, heroin has high affinity and selectivity for -receptors, but its residual analgesia in exon 1 MOR-1 knockout mice that do not respond to morphine suggests a different mechanism of action. MOR-1 splice variants lacking exon 1 have been observed in mice, humans, and rats, raising the possibility that they might be responsible for the residual heroin and morphine-6␤-glucuronide (M6G) analgesia in the exon 1 knockout mice. To test this possibility, we disrupted exon 11 of MOR-1, which eliminates all of the variants that do not contain exon 1. Morphine and methadone analgesia in the exon 11 knockout mouse was normal, but the analgesic actions of heroin, M6G, and fentanyl were markedly diminished in the radiant heat tailflick and hot-plate assays. Similarly, the ability of M6G to inhibit gastrointestinal transit was greatly diminished in these exon 11 knockout mice, whereas the ability of morphine was unchanged. These findings identify receptors selectively involved with heroin and M6G actions and confirm the relevance of the exon 11-associated variants and raise important issues regarding the importance of atypical truncated G-protein-coupled receptors.knockout ͉ analgesia ͉ opiate receptor

show abstract

Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

Pan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

100

140

View full text Add to dashboard Cite

show abstract

“…Although a single gene encoding the mu opioid receptor (MOR-1) has been cloned, several forms of the mu receptor mRNA arising from alternative mRNA slicing have been reported (Pan et al, 2001;Pasternak, 2001a, b). Based on a differential antagonism of the analgesic effects of several opiate drugs as well as on radioligand binding studies, compounds that can functionally differentiate three subtypes of mu opioid receptors (mu 1 , mu 2 , and mu 3 ) have been identified (Pasternak, 2001a, b;Cadet et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

Pastor

Aragón

2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Nonspecific blockade of opioid receptors has been found to prevent development of behavioral sensitization to ethanol. Whether this effect is achieved through a specific opioid receptor subtype, however, is not clear. The present study investigated, for the first time, the role of specific opioid receptor subtypes in the development of ethanol-(2.5 g/kg/day; six sessions) induced locomotor sensitization in mice. We confirmed previous results showing that the nonspecific antagonism of opioid receptors (naltrexone; 0-2 mg/kg) prevented the development of behavioral sensitization to ethanol, an effect attained at doses presumed to occupy only mu opioid receptors. This was confirmed by using the selective mu opioid receptor antagonist CTOP (0-1.5 mg/kg), which also blocked sensitization to ethanol. The selective delta receptor antagonist, naltrindole (0-10 mg/kg), however, did not alter sensitization. We further assessed the role of mu opioid receptors in sensitization to ethanol by exploring the involvement of mu 1 , mu 1 + 2 , and mu 3 opioid receptor subtypes. Results of these experiments revealed that the blockade of mu 1 (naloxonazine; 0-30 mg/kg) or mu 3 opioid receptors (3-methoxynaltrexone; 0-6 mg/kg) did not prevent locomotor sensitization to ethanol. Using naloxonazine under treatment conditions that block mu 1 + 2 opioid receptor subtypes we observed a retarded sensitization. The present data suggest that the concurrent inactivation of all mu opioid receptor subtypes may be required to prevent the neural adaptations underlying the development of behavioral sensitization to ethanol. In addition, these results support previous data suggesting a putative role for the mu opioid receptor endogenous ligand, b-endorphin, and the hypothalamic arcuate nucleus in ethanol sensitization.

show abstract

“…To achieve this unique spatial expression pattern, expression of Oprm1 must be tightly regulated. The mouse Oprm1 gene spans about 250 kb and consists of multiple exons (8). Several Oprm1 isoforms have been reported (9 -11).…”

mentioning

confidence: 99%

A Proteomics Approach for Identification of Single Strand DNA-binding Proteins Involved in Transcriptional Regulation of Mouse μ Opioid Receptor Gene

Choi

Song

Hwang

et al. 2008

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

The pharmacological actions of morphine and morphinelike drugs such as heroin are mediated primarily through the opioid receptor. Previously a single strand DNA element of the mouse opioid receptor gene (Oprm1) proximal promoter was found to be important for regulating Oprm1 in neuronal cells. To identify proteins binding to the single strand DNA element as potential regulators for Oprm1, affinity column chromatography with the single strand DNA element was performed using neuroblastoma NS20Y cells followed by two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. We identified five poly(C)-binding proteins: heterogeneous nuclear ribonucleoprotein (hnRNP) K, ␣-complex proteins (␣CP) ␣CP1, ␣CP2, ␣CP2-KL, and ␣CP3. Binding of these proteins to the single strand DNA element of Oprm1 was sequence-specific as confirmed by supershift assays. In cotransfection studies, hnRNP K, ␣CP1, ␣CP2, and ␣CP2-KL activated the Oprm1 promoter activity, whereas ␣CP3 acted as a repressor. Ectopic expression of hnRNP K, ␣CP1, ␣CP2, and ␣CP2-KL also led to activation of the endogenous Oprm1 transcripts, and ␣CP3 repressed endogenous Oprm1 transcripts. We demonstrate novel roles as transcriptional regulators in

show abstract

Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene

Cited by 173 publications

References 28 publications

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

A Proteomics Approach for Identification of Single Strand DNA-binding Proteins Involved in Transcriptional Regulation of Mouse μ Opioid Receptor Gene

Contact Info

Product

Resources

About