2. Academic Validation
  3. G-protein coupled receptor kinase 2 mediates rheumatoid arthritis-induced depression-like behaviors via the hippocampal CRHR1 signaling pathway

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

  • Acta Pharmacol Sin. 2025 Jul 21. doi: 10.1038/s41401-025-01621-8.
Qian Meng # 1,  Meng-Hui Guo # 2,  Rui Zhang # 2,  Jing Wei 2,  Qian Chen 2,  Xue-Chun Zhao 2,  Cai-Qi Xu 2,  Yao-Yao Wu 2,  Jia-Jie Kuai 2,  Jie-Min Zhao 2,  Yu-Jing Wu 2,  Chong-Huan Ye 2,  Hong-Rui Wei 3,  Xia Zhu 3,  Yan Jin 3,  Zhi Zhang 4 5,  Wei Wei 6
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Key laboratory of Anti-Inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. mengqian@ahmu.edu.cn.
  • 2 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Key laboratory of Anti-Inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
  • 3 CAS Key Laboratory of Brain Function and Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
  • 4 CAS Key Laboratory of Brain Function and Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. zhizhang@ustc.edu.cn.
  • 5 Department of Anatomy, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. zhizhang@ustc.edu.cn.
  • 6 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Key laboratory of Anti-Inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. wwei@ahmu.edu.cn.
  • # Contributed equally.
PMID: 40691271 DOI: 10.1038/s41401-025-01621-8
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 (35 mg·kg-1·d-1, 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.

Keywords

CP-25; GRK2; depression-like behaviors; hippocampus; neuroinflammation; rheumatoid arthritis.

Figures
Products
Inhibitors & Agonists
Other Products