GPR39 通过 CREB-BDNF 信号通路保护海马细胞免受皮质酮诱导的神经元损伤。
GPR39 protects against corticosterone-induced neuronal injury in hippocampal cells through the CREB-BDNF signaling pathway.
机构信息
Department of Nutrition and Food Hygiene, Faculty of Naval Medicine, Second Military Medical University, 800 Xiangyin Rd, 200433 Shanghai, China.
Institute of Aviation Medicine, 28 Fucheng Rd, 100142 Beijing, China.
出版信息
J Affect Disord. 2020 Jul 1;272:474-484. doi: 10.1016/j.jad.2020.03.137. Epub 2020 Apr 30.
BACKGROUND
The release of zinc from glutamatergic terminals in the hippocampal CA3 region can activate postsynaptic GPR39 receptors and regulate cognition and depression. However, the role and mechanism of GPR39 in the stress-induced depression is still poorly understood.
METHODS
In this study, hippocampal cells (HT-22) were treated with corticosterone (CORT). Then the effects of stress on the activity, mitochondrial function and apoptosis of HT-22 cells were observed. The effects of GPR39 on CORT-induced stress injury were analyzed by both siRNA and agonist (TC-G-1008).
RESULTS
Compared with the 500 nM CORT group, the cell viability, apoptosis, mitochondrial membrane potential, and expression levels of BCL-2, CREB and BDNF mRNA were significantly decreased in the GPR39 siRNA+500 nM CORT group, while the expression levels of caspase3, caspase9, AIF and BAX mRNA were significantly increased in the GPR39 siRNA+500 nM CORT group. Compared with the 1 μM CORTgroup, the cell viability, apoptosis, mitochondrial membrane potential, and expression levels of BCL-2, CREB and BDNF were significantly increased in the GPR39 agonist+1 μΜ CORT group, while the expression levels of caspase3, caspase9, AIF and BAX mRNA were significantly decreased in the GPR39 siRNA+500 nM CORT group. Compared with the control group, the mRNA and protein levels of GPR39, CREB and BDNF were significantly increased, and the mRNA and protein levels of CREB and BDNF were significantly decreased after 50 μM zinc sulfate treatment for 6 h.
CONCLUSIONS
GPR39 may play a neuroprotective role in CORT-induced cell injury via the improvement of CREB-BDNF expression, by inhibiting pro-apoptotic proteins and by upregulating anti-apoptotic proteins.
背景
谷氨酸能末梢在海马 CA3 区释放的锌可以激活突触后 GPR39 受体，调节认知和抑郁。然而，GPR39 在应激诱导的抑郁中的作用和机制仍知之甚少。
方法
本研究用皮质酮（CORT）处理海马细胞（HT-22）。然后观察应激对 HT-22 细胞活性、线粒体功能和凋亡的影响。通过 siRNA 和激动剂（TC-G-1008）分析 GPR39 对 CORT 诱导的应激损伤的影响。
结果
与 500 nM CORT 组相比，GPR39 siRNA+500 nM CORT 组细胞活力、凋亡、线粒体膜电位、BCL-2、CREB 和 BDNF mRNA 表达水平显著降低，而 caspase3、caspase9、AIF 和 BAX mRNA 表达水平显著升高。与 1 μM CORT 组相比，GPR39 激动剂+1 μM CORT 组细胞活力、凋亡、线粒体膜电位、BCL-2、CREB 和 BDNF 表达水平显著升高，而 caspase3、caspase9、AIF 和 BAX mRNA 表达水平显著降低。与对照组相比，GPR39、CREB 和 BDNF 的 mRNA 和蛋白水平显著升高，50 μM 硫酸锌处理 6 h 后，CREB 和 BDNF 的 mRNA 和蛋白水平显著降低。
结论
GPR39 可能通过改善 CREB-BDNF 表达、抑制促凋亡蛋白和上调抗凋亡蛋白，在 CORT 诱导的细胞损伤中发挥神经保护作用。
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