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

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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.

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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

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).

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Authors and Affiliations

  1. Faculty of Dentistry, Montreal, Quebec, H3A 0G1, Canada

    Marjo Piltonen, Marc Parisien, Stéphanie Grégoire, Anne-Julie Chabot-Doré, Laura S. Stone & Luda Diatchenko

  2. Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, H3A 0G1, Canada

    Marjo Piltonen, Marc Parisien, Stéphanie Grégoire, Anne-Julie Chabot-Doré, Laura S. Stone & Luda Diatchenko

  3. Goodman Cancer Research Centre and Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 1A3, Canada

    Seyed Mehdi Jafarnejad

  4. Departments of Human Genetics and Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 0G1, Canada

    Pierre Bérubé, Haig Djambazian, Rob Sladek & Rob Sladek

  5. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, H3A 0G1, Canada

    Haig Djambazian, Geneviève Geneau & Patrick Willett

  6. Department of Anaesthesia, McGill University, Montreal, Quebec, H4A 3J1, Canada

    Laura S. Stone & Luda Diatchenko

  7. Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, H3G 1Y6, Canada

    Laura S. Stone & Luda Diatchenko

  8. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA

    Svetlana A. Shabalina

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  1. Marjo Piltonen
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Correspondence to Luda Diatchenko.

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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.

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Piltonen, M., Parisien, M., Grégoire, S. et al. Alternative Splicing of the Delta-Opioid Receptor Gene Suggests Existence of New Functional Isoforms. Mol Neurobiol 56, 2855–2869 (2019). https://doi.org/10.1007/s12035-018-1253-z

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