Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants
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ORIGINAL RESEARCH
Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants Marjo Piltonen1,2,3 · Andrey Krokhotin4 · Marc Parisien1,2,3 · Pierre Bérubé5 · Haig Djambazian5,6 · Rob Sladek5,6 · Nikolay V. Dokholyan7,8 · Svetlana A. Shabalina9 · Luda Diatchenko1,2,3 Received: 12 May 2020 / Accepted: 23 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Opioid receptor · Alternative splicing · Evolutionary conservation · Gene enrichment
Introduction G protein-coupled receptors (GPCRs) are a superfamily of complex signaling proteins with over 800 members. Canonical GPCRs have seven helical transmembrane domains (TM) Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00971-7) contains supplementary material, which is available to authorized users. * Svetlana A. Shabalina [email protected] * Luda Diatchenko [email protected] 1
School of Dentistry, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec H3A 0G1, Canada
Department of Anesthesia, School of Medicine, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec H3A 0G1, Canada
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Alan Edwards Centre for Research on Pain, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec H3A 0G1, Canada
connected with intra- and extracellular loops, an extracellular N-terminus, and an intracellular C-terminus (Supplementary Fig. 1). GPCRs respond to a plethora of stimuli from photons to neurotransmitters and hormones, conveying their message on intracellular effector proteins. They are highly relevant therapeutic targets as approximately 1/3 of 4
Departments of Pathology, Genetics and Developmental Biology, S
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