Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants.

Oct 5, 2020

Contributor: Marjo Piltonen,Andrey Krokhotin,Marc Parisien,Pierre Bérubé,Haig Djambazian,Rob Sladek,Nikolay V Dokholyan,Svetlana A Shabalina,Luda Diatchenko

Alternative Splicing of Opioid Receptor Genes Shows a Conserved Pattern for 6TM Receptor Variants.

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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About The Expert

Marjo Piltonen

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.

Alan Edwards Centre for Research on Pain, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 0G1, Canada.

Andrey Krokhotin

Departments of Pathology, Genetics and Developmental Biology, Stanford Medical School, Howard Hughes Medical Institute, Palo Alto, CA, 94305, USA.

Marc Parisien

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.

Alan Edwards Centre for Research on Pain, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 0G1, Canada.

Pierre Bérubé

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

Haig Djambazian

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

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

Rob Sladek

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

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

Nikolay V Dokholyan

Departments of Pharmacology, and Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA, 17033-0850, USA.

Departments of Chemistry, and Biomedical Engineering, Penn State, University Park, PA, 16802, USA.

Svetlana A Shabalina

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Building 38A, Room S604, 8600 Rockville Pike MSC 3830, Bethesda, MD, 20894-6075, USA. shabalin@ncbi.nlm.nih.gov.

Luda Diatchenko

School of Dentistry, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 0G1, Canada. luda.diatchenko@mcgill.ca.

Department of Anesthesia, School of Medicine, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 0G1, Canada. luda.diatchenko@mcgill.ca.

Alan Edwards Centre for Research on Pain, McGill University, Genome Building, Room 2201, 740 Dr. Penfield Avenue, Montreal, Quebec, H3A 0G1, Canada. luda.diatchenko@mcgill.ca.

References

PubMed