The pathophysiological functions and therapeutic potential of GPR39: Focus on agonists and antagonists

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 3), p.113491, Article 113491
• Main Authors: Cheng, Yuhui, Zhao, Chang, Bin, Yan, Liu, Yuan, Cheng, Lin, Xia, Fan, Tian, Xiaowen, Liu, Xinlei, Liu, Sicen, Ying, Binwu, Shao, Zhenhua, Yan, Wei
• Format: Article
• Language: English
• Subjects: Animals; Endogenous ligands; GPR39; Humans; Ligands; Neoplasms - drug therapy; Neoplasms - metabolism; Pathophysiological function; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Signaling transduction; Synthetic agonists and antagonists
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113491

•Key residues responsible for GPR39's high constitutive activity are identified.•A detailed summary of GPR39's endogenous ligands and pathways is provided.•Physiopathological roles of GPR39 and synthetic ligand development are explored.•GPR39 is a promising therapeutic target for various diseases and disorders. G protein-coupled receptor 39 (GPR39), a member of the growth hormone-releasing peptide family, exhibits widespread expression across various tissues and demonstrates high constitutive activity, primarily activated by zinc ions. It plays critical roles in cell proliferation, differentiation, survival, apoptosis, and ion transport through the recruitment of Gq/11, Gs, G12/13, and β-arrestin proteins. GPR39 is involved in anti-inflammatory and antioxidant responses, highlighting its diverse pathophysiological functions. Recent discoveries of endogenous ligands have enhanced our understanding of GPR39′s physiological roles. Aberrant expression and reactivation of GPR39 have been implicated in a range of diseases, particularly central nervous system disorders, endocrine disruptions, cardiovascular diseases, cancers, and liver conditions. These findings position GPR39 as a promising therapeutic target, with the efficacy of synthetic ligands validated in various in vivo models. Nonetheless, their clinical applicability remains uncertain, necessitating further exploration of novel agonists—especially biased agonists—and antagonists. This review examines the unique residues contributing to the high constitutive activity of GPR39, its endogenous and synthetic ligands, and its pathophysiological implications, aiming to elucidate its pharmacological potential for clinical application in disease treatment.