Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea.
PLoS One. 2021 Aug 26;16(8):e0256390. doi: 10.1371/journal.pone.0256390. eCollection 2021.
Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.
氯胺酮是一种分离麻醉剂和非竞争性 NMDA 受体拮抗剂。在亚麻醉剂量下，氯胺酮可以缓解疼痛并迅速发挥抗抑郁作用，但潜在的分子机制仍不清楚。本研究旨在通过对雄性 C57BL/6J 小鼠前额叶皮质中 microRNA 的生物信息学分析，探讨急性亚麻醉剂量氯胺酮治疗作用的作用模式。推测氯胺酮反应性前额叶 microRNA 靶向的基因的基因本体论和 KEGG 通路分析表明，急性亚麻醉剂量氯胺酮修饰泛素介导的蛋白水解。验证分析表明，miR-148a-3p 和 miR-128-3p 是通过对泛素连接酶 E2 和 E3 的不同调节，负责亚麻醉剂量氯胺酮介导的泛素介导的蛋白水解改变的主要调控因子。总的来说，我们的数据表明，前额叶 microRNA 依赖的泛素介导的蛋白水解的调节至少部分参与了急性亚麻醉剂量氯胺酮治疗的作用模式。
