Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 08901, USA.
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 08901, USA.
Mol Psychiatry. 2020 Jul;25(7):1406-1419. doi: 10.1038/s41380-019-0507-0. Epub 2019 Sep 3.
The OPRM1 A118G single nucleotide polymorphism (SNP rs1799971) gene variant encoding the N40D µ-opioid receptor (MOR) has been associated with dependence on opiates and other drugs of abuse but its mechanism is unknown. The frequency of G-allele carriers is ~40% in Asians, ~16% in Europeans, and ~3% in African-Americans. With opioid abuse-related deaths rising at unprecedented rates, understanding these mechanisms may provide a path to therapy. Here we generated homozygous N40D subject-specific induced inhibitory neuronal cells (iNs) from seven human-induced pluripotent stem (iPS) cell lines from subjects of European descent (both male and female) and probed the impact of N40D MOR regulation on synaptic transmission. We found that D40 iNs exhibit consistently stronger suppression (versus N40) of spontaneous inhibitory postsynaptic currents (sIPSCs) across multiple subjects. To mitigate the confounding effects of background genetic variation on neuronal function, the regulatory effects of MORs on synaptic transmission were recapitulated in two sets of independently engineered isogenic N40D iNs. In addition, we employed biochemical analysis and observed differential N-linked glycosylation of human MOR N40D. This study identifies neurophysiological and molecular differences between human MOR variants that may predict altered opioid responsivity and/or dependence in this subset of individuals.
阿片受体 mu1 型（OPRM1）A118G 单核苷酸多态性（SNP rs1799971）基因变异体编码 N40Dμ 型阿片受体（MOR），与阿片类药物和其他滥用药物的依赖有关，但具体机制尚不清楚。G 等位基因携带者在亚洲人中的频率约为 40%，在欧洲人中约为 16%，在非裔美国人中约为 3%。由于阿片类药物滥用相关的死亡人数以空前的速度上升，了解这些机制可能为治疗提供途径。在这里，我们从七个欧洲血统（男性和女性）的人类诱导多能干细胞（iPS）系中生成了纯合 N40D 个体特异性诱导抑制性神经元细胞（iNs），并研究了 N40D MOR 调节对突触传递的影响。我们发现，与 N40 相比，D40 iNs 在多个研究对象中表现出更强的自发性抑制性突触后电流（sIPSCs）抑制作用。为了减轻背景遗传变异对神经元功能的混杂影响，我们在两组独立设计的基因相同的 N40D iNs 中重现了 MOR 对突触传递的调节作用。此外，我们还进行了生化分析，并观察到人类 MOR N40D 的差异 N 连接糖基化。这项研究鉴定了人类 MOR 变异体之间的神经生理学和分子差异，这些差异可能预测在这部分个体中改变阿片类药物反应性和/或依赖性。
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