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.
Cell Mol Neurobiol. 2021 Jul;41(5):1039-1055. doi: 10.1007/s10571-020-00971-7. Epub 2020 Oct 3.
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.
阿片受体（OPR）家族包括μ、δ和κ阿片受体，以及属于 7 次跨膜 spanning G 蛋白偶联受体（GPCR）超家族的孤啡肽受体。μ阿片受体是临床使用的阿片类镇痛药的主要靶点，其生物学特性已得到广泛研究。通过 OPRM1 基因的选择性剪接产生的 N 端截断 6TM 受体同工型表现出独特的信号转导和镇痛特性，但其他 OPR 是否具有相同的能力尚不清楚。在这项研究中，我们构建了一个全面的阿片受体选择性剪接图谱，展示了所有 OPR 产生 6TM 受体变体的情况，并证明了它们在进化上是保守的。然后，我们通过核糖体足迹分析获得了它们翻译的证据。我们发现，N 端截断的 6TM GPCR 在人类基因组中很少见，而 OPR 在这一组中过度表达。最后，我们还观察到与疼痛、精神障碍和成瘾相关的基因中，6TM GPCR 基因显著富集。了解 6TM 受体的生物学特性，并利用这一知识开发药物，应该为新型疗法铺平道路。
