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Mol Neurobiol. 2019 Apr;56(4):2855-2869. doi: 10.1007/s12035-018-1253-z. Epub 2018 Jul 31.

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

Author information

1
Faculty of Dentistry, Montreal, Quebec, H3A 0G1, Canada.
2
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, H3A 0G1, Canada.
3
Goodman Cancer Research Centre and Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 1A3, Canada.
4
Departments of Human Genetics and Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 0G1, Canada.
5
McGill University and Génome Québec Innovation Centre, Montreal, Quebec, H3A 0G1, Canada.
6
Department of Anaesthesia, McGill University, Montreal, Quebec, H4A 3J1, Canada.
7
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
8
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
9
Faculty of Dentistry, Montreal, Quebec, H3A 0G1, Canada. luda.diatchenko@mcgill.ca.
10
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, H3A 0G1, Canada. luda.diatchenko@mcgill.ca.
11
Department of Anaesthesia, McGill University, Montreal, Quebec, H4A 3J1, Canada. luda.diatchenko@mcgill.ca.
12
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, H3G 1Y6, Canada. luda.diatchenko@mcgill.ca.

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:

Alternative splicing; Delta-opioid receptor; GPCR; OPRD1; Truncated receptor

PMID:
30066306
DOI:
10.1007/s12035-018-1253-z
[Indexed for MEDLINE]

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