Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons
Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons
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DOI：
10.1038/s41380-019-0507-0
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发表时间：
2020-07-01
影响因子：
11
通讯作者：
Pang, Zhiping P.
中科院分区：
文献类型：
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作者：
Halikere, Apoorva;Popova, Dina;Pang, Zhiping P.
编码N40 D μ阿片受体（莫尔）的OPRM 1A 118 G单核苷酸多态性（SNP rs 1799971）基因变异与阿片类药物和其他滥用药物的依赖有关，但其机制尚不清楚。G等位基因携带者的频率在亚洲人中约为40%，在欧洲人中约为16%，在非洲裔美国人中约为3%。随着阿片类药物滥用相关死亡以前所未有的速度上升，了解这些机制可能会提供一种治疗途径。在这里，我们从来自欧洲血统的受试者（男性和女性）的7个人诱导多能干（iPS）细胞系产生纯合N40 D受试者特异性诱导抑制性神经元细胞（iN），并探索N40 D莫尔调节对突触传递的影响。我们发现，D40 iN在多个受试者中表现出对自发抑制性突触后电流（sIPSC）的持续更强的抑制（相对于N40）。为了减轻背景遗传变异对神经元功能的混杂影响，MOR对突触传递的调节作用在两组独立工程化的同基因N40 D iNs中重现。此外，我们采用生化分析和观察人类莫尔N40 D的差异N-连接糖基化。这项研究确定了人类莫尔变异体之间的神经生理学和分子差异，这些差异可能预测这一亚群个体中阿片类药物反应性和/或依赖性的改变。
TheOPRM1A118G single nucleotide polymorphism (SNP rs1799971) gene variant encoding the N40D mu-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 differentialN-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.