Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons
| Autor: | Mavis R. Swerdel, Zhiping P. Pang, Jay A. Tischfield, Matthew S. Scarnati, Jennifer C. Moore, Ronald P. Hart, Apoorva Halikere, Aula Hamod, Dina Popova |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Receptors Opioid mu Single-nucleotide polymorphism Biology Neurotransmission Inhibitory postsynaptic potential Polymorphism Single Nucleotide Article Cell Line 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine SNP Humans Receptor Induced pluripotent stem cell Molecular Biology Neurons Opioid-Related Disorders Psychiatry and Mental health 030104 developmental biology Opioid Inhibitory Postsynaptic Potentials Synapses Female μ-opioid receptor Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Molecular psychiatry |
| ISSN: | 1476-5578 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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