CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510700, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510700, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China.
Cell Rep. 2020 Mar 17;30(11):3625-3631.e6. doi: 10.1016/j.celrep.2020.02.075.
Normally, opioids function in a receptor-dependent manner. They bind to opioid receptors, activate or inhibit receptor activation, and subsequently modulate downstream signal transduction. However, the complex functions of opioids and the low expression of opioid receptors and their endogenous peptide agonists in neural stem cells (NSCs) suggest that some opioids may also modulate NSCs via a receptor-independent pathway. In the current study, two opioids, morphine and naloxone, are demonstrated to facilitate NSC proliferation via a receptor-independent and ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-dependent pathway. Morphine and naloxone penetrate cell membrane, bind to TET1 protein via three key residues (1,880-1,882), and subsequently result in facilitated proliferation of NSCs. In addition, the two opioids also inhibit the DNA demethylation ability of TET1. In summary, the current results connect opioids and DNA demethylation directly at least in NSCs and extend our understanding on both opioids and NSCs.
通常情况下，阿片类药物通过受体依赖性方式发挥作用。它们与阿片受体结合，激活或抑制受体激活，随后调节下游信号转导。然而，阿片类药物的复杂功能以及神经干细胞（NSCs）中阿片受体及其内源性肽激动剂的低表达表明，一些阿片类药物也可能通过非受体依赖性途径来调节 NSCs。在本研究中，两种阿片类药物吗啡和纳洛酮被证明通过非受体依赖性和 ten-eleven translocation methylcytosine dioxygenase 1（TET1）依赖性途径促进 NSC 增殖。吗啡和纳洛酮穿透细胞膜，通过三个关键残基（1,880-1,882）与 TET1 蛋白结合，随后导致 NSCs 的增殖得到促进。此外，这两种阿片类药物还抑制了 TET1 的 DNA 去甲基化能力。综上所述，这些结果至少在 NSCs 中直接将阿片类药物和 DNA 去甲基化联系起来，并扩展了我们对阿片类药物和 NSCs 的认识。
