Characterizing exon 11 promoter of the mu opioid receptor gene, OPRM

Summary

Principal Investigator: Ying Xian Pan
Affiliation: Memorial Sloan-Kettering Cancer Center
Country: USA
Abstract: The long term goal of this proposal is to understand the mechanisms by which the mu opioid receptor (Oprm) gene is regulated and to gain insights into the pharmacological and physiological significance of this regulation. Early pharmacological studies have proposed several mu opioid receptor subtypes: mu1, mu2 and morphine-62-glucuronide (M6G). However, only one mu opioid receptor gene has been identified, raising the possibility that alternative pre-mRNA splicing and multiple promoters of the Oprm gene may be responsible for the multiple mu opioid receptors. Over the last ten years, we have identified 25 splice variants from the mouse Oprm gene, 13 splice variants from the rat Oprm gene and 12 from the human Oprm gene. The functional significance of the splice variants is supported by differences in regional and cell-specific expression, agonist-induced G protein coupling and receptor internalization. Diversity of the Oprm gene was further demonstrated by isolation of a new promoter, exon 11 promoter (E11 promoter). Conservation of the E11-associated variants and the E11 promoter has also been confirmed by identifying these mouse homologs in the rat and human Oprm genes. Our recent knockin/knockout study showed that in mice lacking exon 11, M6G, 6-acetylmorphine and heroin analgesia were greatly diminished, while morphine's response remained unchanged, implying a major functional role for exon 11-associated splice variants and exon 11 promoter in mediating the actions of a subset of mu opioids. This proposal will continue to explore the regulations and functions of E11 promoters by proposing the following specific aims: 1). To characterize the mouse E11 promoter;2). To investigate structure and function of the human E11 promoter;3). To explore the pharmacological function of E11 and E1 promoters using double gene targeting mouse model. The knowledge gained from this proposal will help us obtain a better understanding of the complexity and functional importance of Oprm gene regulation, establish the gene targeted animal models for studying the underlying mechanisms of this gene regulation and function, and provide potential targets for developing novel drugs used in control of pain and drug of abuse. The primary goal of this proposal is to further investigate the regulations and functions of a new promoter, exon 11 promoter, in the mu opioid receptor (Oprm) gene. The knowledge gained from this proposal will help us obtain a better understanding of the complexity and functional importance of Oprm gene regulation, establish the gene targeted animal models for studying the underlying mechanisms of this gene regulation and function, and provide potential targets for developing novel drugs used in control of pain and drug of abuse.
Funding Period: ----------------2001 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Characterizing exons 11 and 1 promoters of the mu opioid receptor (Oprm) gene in transgenic mice
    Jin Xu
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10021 USA
    BMC Mol Biol 7:41. 2006
  2. pmc 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
    Zhigang Lu
    Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York
    Mol Pharmacol 85:368-80. 2014
  3. pmc Mu opioids and their receptors: evolution of a concept
    Gavril W Pasternak
    Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065
    Pharmacol Rev 65:1257-317. 2013
  4. pmc Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action
    Jin Xu
    Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Biol Chem 288:21211-27. 2013
  5. pmc ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers
    Stephanie E Sillivan
    Departments of Psychiatry and Neuroscience SES, JDW, MMJ, YR, FFC, YLH Department of Pharmacology and Systems Therapeutics SES, MMJ, YR, arm, FFC, AM, YLH, Ichan School of Medicine at Mount Sinai, New York, New York
    Biol Psychiatry 74:511-9. 2013
  6. pmc Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P
    Jin Xu
    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065
    Synapse 68:144-52. 2014
  7. pmc Mu opioid receptors in pain management
    Gavril Pasternak
    Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, NY 10065, USA
    Acta Anaesthesiol Taiwan 49:21-5. 2011
  8. pmc Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects
    Susruta Majumdar
    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 108:19778-83. 2011
  9. pmc Identification and characterization of seven new exon 11-associated splice variants of the rat μ opioid receptor gene, OPRM1
    Jin Xu
    Department of Neurology and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Mol Pain 7:9. 2011
  10. pmc Changes in mouse mu opioid receptor Exon 7/8-like immunoreactivity following food restriction and food deprivation in rats
    Maria M Hadjimarkou
    Department of Psychology and Neuropsychology Doctoral Sub Program, Queens College, City University of New York, Flushing, New York 11367, USA
    Synapse 63:585-97. 2009

Scientific Experts

  • Gavril Pasternak
  • Ying Xian Pan
  • Jin Xu
  • Mingming Xu
  • Yasmin L Hurd
  • Zhigang Lu
  • Stephanie E Sillivan
  • Grace C Rossi
  • Susruta Majumdar
  • Clare V LeFave
  • Maria M Hadjimarkou
  • Elizabeth Bolan
  • Annie Kim Gilbert
  • Francesca F Caputi
  • Ming Xu
  • Michelle M Jacobs
  • Monika Horvath
  • Amin R Mazloom
  • AVI MA'AYAN
  • Charles E Inturrisi
  • Eva Keller
  • Yanhua Ren
  • John D Whittard
  • Taylor Brown
  • Lillian W Chiang
  • Sandra Vorlova
  • Steven Grinnell
  • Lisa Polikar
  • Luca Cartegni
  • Massimo Squatrito
  • Gina L Rocco
  • Valerie Le Rouzic
  • John Pintar
  • Cameron W Brennan
  • Maxim Burgman
  • Michael Ansonoff
  • Eric C Holland
  • Catherine Abbadie
  • Richard J Bodnar
  • Lora J Kasselman

Detail Information

Publications13

  1. pmc Characterizing exons 11 and 1 promoters of the mu opioid receptor (Oprm) gene in transgenic mice
    Jin Xu
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10021 USA
    BMC Mol Biol 7:41. 2006
    ..The aim of this study is to further characterize the E11 and E1 promoters in vivo using a transgenic mouse model...
  2. pmc 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
    Zhigang Lu
    Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York
    Mol Pharmacol 85:368-80. 2014
    ....
  3. pmc Mu opioids and their receptors: evolution of a concept
    Gavril W Pasternak
    Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065
    Pharmacol Rev 65:1257-317. 2013
    ..These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated. ..
  4. pmc Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action
    Jin Xu
    Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Biol Chem 288:21211-27. 2013
    ..Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families. ..
  5. pmc ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers
    Stephanie E Sillivan
    Departments of Psychiatry and Neuroscience SES, JDW, MMJ, YR, FFC, YLH Department of Pharmacology and Systems Therapeutics SES, MMJ, YR, arm, FFC, AM, YLH, Ichan School of Medicine at Mount Sinai, New York, New York
    Biol Psychiatry 74:511-9. 2013
    ..The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders...
  6. pmc Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P
    Jin Xu
    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065
    Synapse 68:144-52. 2014
    ..Synapse 68:144-152, 2014. © 2013 Wiley Periodicals, Inc. ..
  7. pmc Mu opioid receptors in pain management
    Gavril Pasternak
    Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, NY 10065, USA
    Acta Anaesthesiol Taiwan 49:21-5. 2011
    ..It now appears that this gene undergoes extensive splicing, in which a single gene can generate multiple proteins. Evidence now suggests that these splice variants may help explain the clinical variability in responses among patients...
  8. pmc Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects
    Susruta Majumdar
    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 108:19778-83. 2011
    ....
  9. pmc Identification and characterization of seven new exon 11-associated splice variants of the rat μ opioid receptor gene, OPRM1
    Jin Xu
    Department of Neurology and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Mol Pain 7:9. 2011
    ..We now have examined 5' splicing in the rat...
  10. pmc Changes in mouse mu opioid receptor Exon 7/8-like immunoreactivity following food restriction and food deprivation in rats
    Maria M Hadjimarkou
    Department of Psychology and Neuropsychology Doctoral Sub Program, Queens College, City University of New York, Flushing, New York 11367, USA
    Synapse 63:585-97. 2009
    ..This study indicates the sensitivity of this mE7/8-LI probe in the hypothalamic parvocellular paraventricular nucleus and rostral NTS to food restriction and deprivation in rats...
  11. pmc Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions
    Ying Xian Pan
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Proc Natl Acad Sci U S A 106:4917-22. 2009
    ....
  12. pmc Isolation and characterization of new exon 11-associated N-terminal splice variants of the human mu opioid receptor gene
    Jin Xu
    Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    J Neurochem 108:962-72. 2009
    ..The presence of exon 11-associated variants in humans raises questions regarding their potential role in heroin and morphine-6beta-glucuronide actions in people as they do in mice...
  13. pmc Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas
    Clare V LeFave
    Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    EMBO J 30:4084-97. 2011
    ....