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

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.