G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint damage and even disability. Although there are various clinical therapies for RA, some patients still have poor or no response. Thus, the development of new drug targets remains a high priority. In this review, we discuss the role of G-protein-coupled receptors (GPCRs), including chemokine receptors, melanocortin receptors, lipid metabolism-related receptors, adenosine receptors, and other inflammation-related receptors, on mechanisms of RA, such as inflammation, lipid metabolism, angiogenesis, and bone destruction. Additionally, we summarize the latest clinical trials on GPCR targeting to provide a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA.

Keywords: G-protein-coupled receptors; angiogenesis; bone destruction; inflammation; lipid metabolism; rheumatoid arthritis.

Figure 1

Relationship between multiple GPCRs and RA. GPCRs signal through the αβγ subunit of heterotrimeric G proteins. In response to ligand signals, GTP binds to the Gα subunit, and Gβγ dissociates to form a dimer for downstream signaling, binding to biological mediators. GRK2 is a kinase that phosphorylates activated GPCRs, making them a high-affinity substrate for the binding of the uncoupling protein arrestin. Arrestin binding abolishes (“arrests”) G protein-mediated signaling. The binding of GRK2 to Gβγ recruits cytosolic GRK2 to the plasma membrane, where the activated receptor is located. This is its primary function. It can also inhibit Gβγ-mediated signaling by sequestering Gβγ, which is a secondary effect. GPCRs interact with immune cells in RA to influence multiple mechanisms including bone destruction, inflammation, and angiogenesis.