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 mu、delta 和 kappa 阿片受体，以及属于 7 次跨膜 G 蛋白偶联受体 (GPCR) 超家族的伤害感受素受体。μ阿片受体是临床使用阿片类镇痛药的主要靶点，其生物学已被广泛研究。通过OPRM1基因选择性剪接产生的 N 端截短的 6TM 受体异构体显示出独特的信号传导和镇痛特性，但尚不清楚其他 OPR 是否具有相同的能力。在这项研究中，我们建立了选择性剪接事件的综合图谱，这些事件在所有 OPR 中产生 6TM 受体变体，并证明了它们的进化保守性。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 端截短的 6TM GPCR 在人类基因组中很少见，而 OPR 在该组中比例过高。最后，我们还观察到与疼痛、精神疾病和成瘾相关的基因中 6TM GPCR 基因显着富集。了解 6TM 受体的生物学并利用这些知识进行药物开发应该为新疗法铺平道路。