Gpr39, also known as the zinc-sensing receptor (ZnR), is a member of the ghrelin family of G-protein coupled receptors. It can sense changes in extracellular Zn2+ in physiological concentrations and is involved in the regulation of diverse physiological activities. It activates signaling pathways such as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol3-kinase/protein kinase B (PI3K/AKT) [3,4]. Gpr39 is important for maintaining neurovascular homeostasis, regulating immune response, and is potentially involved in many metabolic, endocrine, and neurological functions [2]. Genetically modified rodent models have been crucial for understanding its functions [3].

In pancreatic acinar cells, Gpr39 knockout (KO) mice showed significantly reduced acute pancreatitis (AP) induced by bile acids, indicating Gpr39 is necessary and sufficient to mediate bile acid (BA) signaling and is involved in biliary AP pathogenesis [1]. In the context of angiotensin II (Ang II)-induced hypertension, Gpr39 KO mice had mitigated vascular fibrosis, augmented endothelium-dependent vasodilation, and inhibited endothelial inflammation, oxidative stress, and apoptosis. The ablation of Gpr39 also decreased NOD-like receptor protein 3 (Nlrp3) gene expression in Ang II-stimulated endothelial cells [5].

In conclusion, Gpr39 plays essential roles in maintaining physiological functions, especially in processes related to biliary AP and Ang II-induced hypertension. The use of Gpr39 KO mouse models has revealed its significance in these disease areas, providing potential new directions for therapeutic intervention.

References:

1. Zi, Zhentao, Rao, Yi. 2024. Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis. In Science advances, 10, eadj0146. doi:10.1126/sciadv.adj0146. https://pubmed.ncbi.nlm.nih.gov/38306436/

2. Xu, Yifan, Barnes, Anthony P, Alkayed, Nabil J. 2021. Role of GPR39 in Neurovascular Homeostasis and Disease. In International journal of molecular sciences, 22, . doi:10.3390/ijms22158200. https://pubmed.ncbi.nlm.nih.gov/34360964/

3. Laitakari, Anna, Liu, Lingzhi, Frimurer, Thomas M, Holst, Birgitte. 2021. The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target. In International journal of molecular sciences, 22, . doi:10.3390/ijms22083872. https://pubmed.ncbi.nlm.nih.gov/33918078/

4. Xia, Pengpeng, Yan, Li, Ji, Xingduo, Lian, Siqi, Zhu, Guoqiang. 2022. Functions of the Zinc-Sensing Receptor GPR39 in Regulating Intestinal Health in Animals. In International journal of molecular sciences, 23, . doi:10.3390/ijms232012133. https://pubmed.ncbi.nlm.nih.gov/36292986/

5. Hua, Dongxu, Huang, Wanlin, Xie, Qiyang, Li, Peng, Sheng, Yanhui. 2024. Targeting GPR39 in structure-based drug discovery reduces Ang II-induced hypertension. In Communications biology, 7, 1441. doi:10.1038/s42003-024-07132-2. https://pubmed.ncbi.nlm.nih.gov/39500998/