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.
Bibliographical noteFunding Information:
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).
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
- Alternative splicing
- Delta-opioid receptor
- Truncated receptor