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Alternative Splicing of the Delta-Opioid Receptor Gene Suggests Existence of New Functional Isoforms

  • Marjo Piltonen
  • Marc Parisien
  • Stéphanie Grégoire
  • Anne-Julie Chabot-Doré
  • Seyed Mehdi Jafarnejad
  • Pierre Bérubé
  • Haig Djambazian
  • Rob Sladek
  • Geneviève Geneau
  • Patrick Willett
  • Laura S. Stone
  • Svetlana A. Shabalina
  • Luda Diatchenko
Article

Abstract

The delta-opioid receptor (DOPr) participates in mediating the effects of opioid analgesics. However, no selective agonists have entered clinical care despite potential to ameliorate many neurological and psychiatric disorders. In an effort to address the drug development challenges, the functional contribution of receptor isoforms created by alternative splicing of the three-exonic coding gene, OPRD1, has been overlooked. We report that the gene is transcriptionally more diverse than previously demonstrated, producing novel protein isoforms in humans and mice. We provide support for the functional relevance of splice variants through context-dependent expression profiling (tissues, disease model) and conservation of the transcriptional landscape in closely related vertebrates. The conserved alternative transcriptional events have two distinct patterns. First, cassette exon inclusions between exons 1 and 2 interrupt the reading frame, producing truncated receptor fragments comprising only the first transmembrane (TM) domain, despite the lack of exact exon orthologues between distant species. Second, a novel promoter and transcriptional start site upstream of exon 2 produces a transcript of an N-terminally truncated 6TM isoform. However, a fundamental difference in the exonic landscaping as well as translation and translation products poses limits for modelling the human DOPr receptor system in mice.

Keywords

Delta-opioid receptor OPRD1 Alternative splicing Truncated receptor GPCR 

Notes

Acknowledgements

The authors would like to express their gratitude to Anna K. Naumova for her helpful comments and ideas. Cellecta Inc. is gratefully acknowledged for PCR on OPRD1 transcripts in human tissues.

Funding Information

This work was supported by The Canadian Institutes of Health Research (G237818/CERC09/CIHR to L.D.) and by the Intramural funds of the US Department of Health and Human Services to the National Library of Medicine (to S.A.S).

Compliance with Ethical Standards

Experimental procedures were approved by the Animal Care Committee at McGill University and conformed to the ethical guidelines of the Canadian Council of Animal Care and the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1253_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1205 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Marjo Piltonen
    • 1
    • 2
  • Marc Parisien
    • 1
    • 2
  • Stéphanie Grégoire
    • 1
    • 2
  • Anne-Julie Chabot-Doré
    • 1
    • 2
  • Seyed Mehdi Jafarnejad
    • 3
  • Pierre Bérubé
    • 4
  • Haig Djambazian
    • 4
    • 5
  • Rob Sladek
    • 4
    • 4
  • Geneviève Geneau
    • 5
  • Patrick Willett
    • 5
  • Laura S. Stone
    • 1
    • 2
    • 6
    • 7
  • Svetlana A. Shabalina
    • 8
  • Luda Diatchenko
    • 1
    • 2
    • 6
    • 7
  1. 1.Faculty of DentistryMontrealCanada
  2. 2.Alan Edwards Centre for Research on PainMcGill UniversityMontrealCanada
  3. 3.Goodman Cancer Research Centre and Department of Biochemistry, Faculty of MedicineMcGill UniversityMontrealCanada
  4. 4.Departments of Human Genetics and Medicine, Faculty of MedicineMcGill UniversityMontrealCanada
  5. 5.McGill University and Génome Québec Innovation CentreMontrealCanada
  6. 6.Department of AnaesthesiaMcGill UniversityMontrealCanada
  7. 7.Department of Pharmacology and Therapeutics, Faculty of MedicineMcGill UniversityMontrealCanada
  8. 8.National Center for Biotechnology Information, National Library of MedicineNational Institutes of HealthBethesdaUSA

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