安徽医科大学魏伟团队的最新研究探明了G蛋白偶联受体激酶2通过海马CRHR1信号通路介导类风湿关节炎诱导的抑郁样行为。相关论文于2025年7月21日发表于国际顶尖学术期刊《中国药理学报》杂志上。

在这项研究中，课题组研究人员研究了胶原诱导关节炎（CIA）模型小鼠共病抑郁与类风湿关节炎的分子机制。该研究组发现，在建立CIA模型后5周出现了类似抑郁的行为。

此外，该团队发现在CIA小鼠海马中，G蛋白偶联受体激酶2 （GRK2）显著上调，而其靶点促肾上腺皮质激素释放激素受体1（CRHR1）的表达显著降低，下游cAMP/PKA/CREB/BDNF信号通路也明显降低。该团队证明GRK2可以直接与CRHR1相互作用，抑制CRHR1依赖性信号。降低海马GRK2或用CP-25 （35mg·kg^-1·d^-1，持续21天）进行药理学抑制可以缓解CIA小鼠的抑郁样行为，而GRK2过表达可诱导幼稚小鼠抑郁样行为。他们的研究确定了海马GRK2是CIA模型小鼠与类风湿性关节炎相关的抑郁样行为的调节剂，提示了治疗靶点和潜在的治疗策略。

研究人员表示，类风湿性关节炎伴抑郁症状是临床上常见的症状。

附：英文原文

Title: G-protein coupled receptor kinase 2 mediates rheumatoid arthritis-induced depression-like behaviors via the hippocampal CRHR1 signaling pathway

Author: Meng, Qian, Guo, Meng-hui, Zhang, Rui, Wei, Jing, Chen, Qian, Zhao, Xue-chun, Xu, Cai-qi, Wu, Yao-yao, Kuai, Jia-jie, Zhao, Jie-min, Wu, Yu-jing, Ye, Chong-huan, Wei, Hong-rui, Zhu, Xia, Jin, Yan, Zhang, Zhi, Wei, Wei

Issue&Volume: 2025-07-21

Abstract: Rheumatoid arthritis with depressive symptoms is frequently encountered in clinic. In this study, we investigated the molecular mechanisms responsible for comorbid depression with rheumatoid arthritis in collagen-induced arthritis (CIA) model mice. We showed that depression-like behaviors were developed at 5 weeks after establishing CIA model. Furthermore, we found that in the hippocampus of CIA mice, G-protein coupled receptor kinase 2 (GRK2) was significantly upregulated, while the expression of its target, corticotropin releasing hormone receptor 1 (CRHR1) was notably decreased, as was the downstream cAMP/PKA/CREB/BDNF signaling. We demonstrated that GRK2 could directly interact with CRHR1, suppressing CRHR1-dependent signaling. Knockdown of hippocampal GRK2 or pharmacological inhibition with CP-25 (35mg·kg1·d1, i.g. for 21 days) could alleviate the depression-like behaviors in CIA mice, whereas GRK2 overexpression induced depression-like behaviors in naive mice. Our study identifies hippocampal GRK2 as a regulator of depression-like behaviors associated with rheumatoid arthritis in CIA model mice, suggesting both a therapeutic target and potential treatment strategy.

DOI: 10.1038/s41401-025-01621-8

Source: https://www.nature.com/articles/s41401-025-01621-8