International Immunopharmacology
Volume 143, Part 3, 25 December 2024, 113491
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.
G protein-coupled receptor 39 (GPR39) belongs to the extensive family of seven-transmembrane (7-TM) G protein-coupled receptors (GPCRs). GPR39 was initially identified as a growth hormone secretagogue receptor (GHS-R) related gene. Consequently, GPR39 is categorized within the GHS-R subfamily, which includes six structurally homologous receptors: GPR38, GHS-R, neurotensin receptor 1/2, and neuromedin-U receptor 1/2. Currently, the physiological functions of these other six members have been well-characterized through numerous studies that have identified their endogenous ligands. Although zinc ions (Zn 2+) have been shown to activate GPR39, it is still classified as an orphan receptor due to the absence of information regarding natural nonionic ligands. GPR39 exhibits high constitutive activity and can recruit the Gq/11 proteins, G12/13 proteins, and β-arrestin. Furthermore, GPR39 is extensively phosphorylated under physiological conditions; however, the functional implications of this phosphorylation have not been fully elucidated. Notably, this phosphorylation does not facilitate β-arrestin 2 recruitment or internalization, as GPR39 can interact with a phosphorylation-independent β-arrestin 2 variant that possesses a mutated anion sensor.
GPR39 is widely expressed across various organs and tissues, particularly in peripheral tissues and the central nervous system (CNS), including the pancreas, liver, adipose tissue, gastrointestinal tract, frontal cortex, amygdala, and hippocampus. GPR39 is implicated in a multitude of cellular functions, such as cell proliferation, differentiation, survival, apoptosis,ion transport, pH regulation, chondrogenesis, epithelial repair, vascular endothelial cell activity, gastrointestinal tract motility, tight junction formation, salivary secretion, sperm motility, acrosome exocytosis, and T-cell reconstitution.
Furthermore, GPR39 appears to participate in numerous physiological functions, encompassing neuronal function, metabolism, endocrine function, immune response, bone formation, tissue repair, and fertility. Consequently, dysregulation of GPR39 has been associated with a variety of diseases, including CNS disorders, metabolic and endocrine system abnormalities, musculoskeletal disorders, several types of cancers, cardiovascular diseases, intracerebral hemorrhage, neuropathic and inflammatory pain, liver diseases, infection-induced inflammation, impaired wound healing, biliary acute pancreatitis, diarrhea, and osteoarthritis (OA). Utilizing various in vitro and in vivo models, GPR39 has been investigated as a potential therapeutic target for a range of diseases.
Despite the growing interest in GPR39, research on its natural ligands remains limited, leaving the precise mechanisms of GPR39 activation in various diseases ambiguous. This knowledge gap presents challenges for drug development and clinical application. Therefore, this review aims to summarize findings related to the residues involved in constitutive activity, the identification of endogenous ligands, synthetic agonists and antagonists, and the pathophysiological mechanisms of GPR39 across different disease contexts, particularly in CNS disorders, endocrine disorders, cardiovascular diseases, cancers, and liver-related conditions. By elucidating the role of GPR39, we hope to provide insights that could inform clinical drug development.
Recent research has investigated the structural basis of GPR39 through mutational analysis. It has been found that the receptor’s high constitutive activity is linked to the aromatic and hydrophobic residues located on the inner face of the extracellular ends of TM segments VI and VII. Additionally, the mutational analysis has demonstrated that the degree of constitutive activity can be modulated by the aromatic cluster of asparagine (N340 7.49). Furthermore, the Alanine (Ala) substitution
As described above, Zn 2+ can function as a low-potency agonist of GPR39 in vitro by enhancing inositol 1,4,5-triphosphate (IP 3) accumulation. In 2007, fetal bovine serum (FBS) was utilized to identify endogenous ligands for GPR39 due to its accessibility and reproducibility in experimental settings. This study demonstrated that Zn 2+ is the active constituent of FBS, and can activate GPR39 via the Gq-phospholipase C (PLC)-IP 3 pathway. Consequently, GPR39 was identified as a Gq-coupled Zn 2+
The present evidence suggests that GPR39 can participate in various pathophysiological processes, especially in the presence of Zn 2+ by modulating anti-inflammatory effects, antioxidants, ion homeostasis, etc. Based on the wide distribution of GPR39, researchers have demonstrated the different roles of GPR39 in many diseases. Diseases associated with GPR39 and their potential pathways are illustrated in Fig. 1. In the subsequent
To date, the repertoire of well-characterized synthetic agonists for GPR39 remains limited. In 2013, Boehm et al. established a novel chemical probe identification platform for orphan GPCR, which led to the first discovery of small molecule agonists (piperazine derivatives) for GPR39. They reported that piperazine derivative 1 (Compound 1) functions as a partial agonist activating only the Ca 2+-dependent signal transduction pathway of GPR39, in contrast to the Zn 2+-mediated pathway.
GPR39 is a highly constitutive receptor activated by Zn 2+ through Gq-coupled, Gs-coupled, G12/13-coupled, and β-arrestin signaling pathways. As a zinc receptor, GPR39 serves as a critical regulator of Zn 2+-dependent signaling and is implicated in numerous physiological and pathological processes associated with Zn 2+ homeostasis. Multiple preclinical and clinical studies have demonstrated that Zn 2+ possesses neuroprotective, antidepressant and anxiolytic properties. However, the
Wei Yan, Zhenhua Shao, and Binwu Ying supervised the overall project and designed the manuscript; Yuhui Cheng, Chang Zhao, Yuan Liu, and Xiaowen Tian wrote the manuscript and created the figures with the assistance of Lin Cheng, and Fan Xia. All authors have read and approved the final manuscript.
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Competing interests.
The authors declare no conflicts of interests.
Yuhui Cheng: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Data curation. Chang Zhao: Writing – review & editing, Writing – original draft, Supervision, Resources, Methodology, Funding acquisition. Yan Bin: Software, Resources. Yuan Liu: Writing – original draft, Visualization. Lin Cheng: Writing – review & editing, Supervision, Funding acquisition. Fan Xia: Writing – review &
This work was supported by the National Natural Science Foundation of China (32100988 and 32,371,288 to Wei Yan, 82,272,416 to Binwu Ying, 82,271,190 and 32,100,965 to Lin Cheng, 323B2038 to Chang Zhao, 82,201,453 to Fan Xia, 82,304,283 to Xinlei Liu), Science and Technology Department of Sichuan Province (2024NSFJQ0052 to Zhenhua Shao), and Ministry of Technology Department of China grant (2019YFA0508800 to Zhenhua Shao). 1.3.5 Project for Disciplines of Excellence, West China Hospital,
We wish to thank the timely help given by Mr. Ryan from École Polytechnique
