The pathophysiological functions and drug development of GPR39

G protein-coupled receptor 39 (GPR39), a member of the growth hormone-releasing peptide family, is widely expressed in different tissues. GPR39 has high constitutive activity and can be activated by zinc ions. GPR39 participates in cell proliferation, differentiation, survival, apoptosis, and ion transport by recruiting Gq/11, Gs, G12/13, and β-arrestin proteins. GPR39 can perform anti-inflammatory, antioxidant, and other pathophysiological functions. In recent research, the discovery of endogenous ligands has shed light on the physiological function of GPR39. Increasing evidence has confirmed that the aberrant expression and reactivation of GPR39 can cause various diseases, especially central nervous system disorders, endocrine system disorders, cardiovascular diseases, cancers, and liver-related diseases. This finding suggested that GPR39 could be a promising therapeutic target for multiple diseases and the potency of synthetic GPR39 ligands has been validated in many in vivo models. However, the efficiency of synthetic ligands in clinical applications is still unknown, and the development of novel agonists, especially biased agonists, and antagonists needs further exploration. This review focuses on the special residues of the high constitutive activity of GPR39, its endogenous and synthetic agonists, and its pathophysiological role, aiming to explore its pharmacological potential and further clinical application in treating diseases.