Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou 350122, China.
Department of Pharmacy, Wuhan No. 1 Hospital, Wuhan 430000, China.
Biomed Pharmacother. 2023 Dec 31;169:115859. doi: 10.1016/j.biopha.2023.115859. Epub 2023 Nov 9.
Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.
蛋白质翻译后修饰调节突触蛋白稳定性、分拣和运输，并与情绪障碍有关。然而，调节情绪障碍的分子机制仍不清楚。在这里，我们报告了蛋白质棕榈酰化/硝化交联在调节大鼠焦虑样行为中的未知作用。根据高架十字迷宫测试中开放臂持续时间的百分比，将大鼠分为高、中、低焦虑组。通过酰基辅酶 A 交换测定法检测棕榈酰化和硝化水平，我们发现高焦虑大鼠基底外侧杏仁核（BLA）中的棕榈酰化水平较低，硝化水平较高。此外，我们观察到棕榈酰化抑制剂 2-溴棕榈酸（2-BP）诱导焦虑样行为，同时降低 BLA 中 mEPSC 和 mIPSC 的幅度和频率。此外，我们还发现，在 BLA 中抑制 nNOS 活性用 7-硝基吲唑（7-NI）引起抗焦虑作用并降低突触传递。有趣的是，地西泮（DZP）迅速提高 BLA 中的蛋白质棕榈酰化水平并降低蛋白质硝化水平。具体而言，与 DZP 相似，自愿轮跑发挥 DZP 样抗焦虑作用，并在 BLA 中诱导高棕榈酰化和低硝化水平。最后，用 2-BP 阻断蛋白质棕榈酰化会导致蛋白质硝化水平增加，而用 7-NI 抑制 nNOS 活性会提高蛋白质棕榈酰化水平。总之，这些结果表明蛋白质棕榈酰化/硝化交联在调节大鼠焦虑行为中起关键作用，它可能成为抗焦虑干预的潜在靶点。
