TY - JOUR
T1 - Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants
AU - Piltonen, Marjo
AU - Krokhotin, Andrey
AU - Parisien, Marc
AU - Bérubé, Pierre
AU - Djambazian, Haig
AU - Sladek, Rob
AU - Dokholyan, Nikolay V.
AU - Shabalina, Svetlana A.
AU - Diatchenko, Luda
N1 - 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]. The authors wish to thank Geneviève Geneau and Patrick Willett for their expert help with sequencing.
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - The opioid receptor (OPR) family comprises the mu-, delta-, and kappa-opioid, and nociceptin receptors that belong to the superfamily of 7-transmembrane spanning G protein-coupled receptors (GPCRs). The mu-opioid receptor is the main target for clinically used opioid analgesics, and its biology has been extensively studied. The N-terminally truncated 6TM receptors isoform produced through alternative splicing of the OPRM1 gene displays unique signaling and analgesic properties, but it is unclear if other OPRs have the same ability. In this study, we have built a comprehensive map of alternative splicing events that produce 6TM receptor variants in all the OPRs and demonstrated their evolutionary conservation. We then obtained evidence for their translation through ribosomal footprint analysis. We discovered that N-terminally truncated 6TM GPCRs are rare in the human genome and OPRs are overrepresented in this group. Finally, we also observed a significant enrichment of 6TM GPCR genes among genes associated with pain, psychiatric disorders, and addiction. Understanding the biology of 6TM receptors and leveraging this knowledge for drug development should pave the way for novel therapies.
AB - The opioid receptor (OPR) family comprises the mu-, delta-, and kappa-opioid, and nociceptin receptors that belong to the superfamily of 7-transmembrane spanning G protein-coupled receptors (GPCRs). The mu-opioid receptor is the main target for clinically used opioid analgesics, and its biology has been extensively studied. The N-terminally truncated 6TM receptors isoform produced through alternative splicing of the OPRM1 gene displays unique signaling and analgesic properties, but it is unclear if other OPRs have the same ability. In this study, we have built a comprehensive map of alternative splicing events that produce 6TM receptor variants in all the OPRs and demonstrated their evolutionary conservation. We then obtained evidence for their translation through ribosomal footprint analysis. We discovered that N-terminally truncated 6TM GPCRs are rare in the human genome and OPRs are overrepresented in this group. Finally, we also observed a significant enrichment of 6TM GPCR genes among genes associated with pain, psychiatric disorders, and addiction. Understanding the biology of 6TM receptors and leveraging this knowledge for drug development should pave the way for novel therapies.
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U2 - 10.1007/s10571-020-00971-7
DO - 10.1007/s10571-020-00971-7
M3 - Article
C2 - 33010019
AN - SCOPUS:85091840624
VL - 41
SP - 1039
EP - 1055
JO - Cellular and Molecular Neurobiology
JF - Cellular and Molecular Neurobiology
SN - 0272-4340
IS - 5
ER -