From orphan receptor to inflammation regulation: The role of GPR35 in the pathogenesis of depression

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and have attracted significant attention as pharmacological targets, and they represent the largest target class for many drugs used in the treatment of various diseases. One of the intriguing members of this family is G protein-coupled receptor 35 (GPR35), which belongs to the class A GPCR superfamily and is an orphan receptor. GPR35 has been shown to be expressed in many organ-tissue systems, including the gastrointestinal tract, immune system, and central nervous system (CNS). Therefore, its association with the progression of pathophysiological diseases in these organ-tissue systems is not surprising. Accumulating evidence has implicated GPR35 in the regulation of inflammatory responses. Additionally, GPR35 has been demonstrated to be involved in depression-like behaviours induced by inflammation in mice. Despite these findings, the precise mechanisms by which GPR35 contributes to the pathogenesis of depression remain unclear. In this article, we highlight the structure, widespread expression, and endogenous ligands of GPR35, as well as its role in the pathophysiology of mental disorders, particularly in depression. In addition, we explored the role of GPR35 agonists and antagonists in the antidepressant mechanism, expanding the potential therapeutic value of GPR35 in depression. In summary, GPR35 has shown clear preclinical potential in the treatment of depression, which will provide a theoretical basis for accelerating its translation from the laboratory to the clinic, holding promise as a new breakthrough in the treatment of mental disorders.