The dopamine D3 receptor regulates dopamine-induced activation and glycolytic metabolism of synovial fibroblasts in rheumatoid arthritis

Journal article

INTRODUCTION: Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast cells reduced inflammation in a mouse model of RA. In this study, we explored the role of D3R in regulating dopamine-induced activation and glycolysis in synovial fibroblasts from patients with RA (RASFs).

METHOD: RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R by D3R agonist (7-OH-DPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs.

RESULTS: Dopamine stimulation induced a dose-dependent increase in cell viability and α-SMA expression in RASFs. Dopamine also caused significant and dose-dependent upregulation of glycolysis-related enzymes in RASFs. Treatment with 7-OH-DPAT inhibited dopamine-induced increases inα-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhancedeffects stimulated by dopamine. NGB2904 treatment upregulated glycolysis and the expression of glycolytic enzymes induced by dopamine, whereas 7-OH-DPAT treatment downregulated glycolysis and glycolytic enzymes in RASFs. NGB2904 attenuated the ability of 7-OH-DPAT to inhibit the dopamine-induced elevation in cAMP levels of RASFs. Involvements of the cAMP pathway was confirmed by findings that H89 (a PKA inhibitor) abrogated the upregulation of activation, glycolysis, and expression of glycolytic enzymes mediated by the D3R antagonist, NGB2904, in RASFs.

CONCLUSION: D3R downregulates dopamine induced activation and glycolysis of RASFs by suppressing PKA activity. Therefore, inhibition of glycolysis by manipulating the D3R pathway may provide a novel therapeutic strategy to reduce the activation of RASFs.

Authors: Xue, L; Xu, S; Li, M; Wang, B; Kang, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Clinical & Experimental Immunology
• Place of publication: England
• Publication date: 2026-02-09
• Acceptance date: 2026-02-01
• DOI: 10.1093/cei/uxag008
• EISSN: 1365-2249
• ISSN: 0009-9104
• Pmid: 41664410
• Language: English
• Keywords: autoimmune disease; rheumatoid arthritis; neurosciences; inflammatory and immune system; arthritis