Gpr132, also known as G2A, is a G-protein-coupled receptor with diverse functions. It serves as a sensor for various ligands such as lactate, 9(S)-hydroxy-10,12-octadecadienoic acid, and N-palmitoylglycine, and is involved in multiple signaling pathways. Gpr132 is crucial in immune cell regulation, tissue repair, and has implications in various disease processes [3,5]. Genetic models, like gene knockout (KO) mouse models, have been instrumental in understanding its functions.

In breast cancer, Gpr132 deletion reduces M2 macrophages and impedes lung metastasis, indicating its role in promoting tumor-macrophage interplay and metastasis [1]. In diabetes, Gpr132 deficiency in macrophages reverses metabolic disorders in high-fat-diet-fed mice, suggesting its involvement in intra-islet lipid-transmembrane receptor signalling and macrophage reprogramming [2]. In NK cell function regulation, Gpr132-deficient NK92 cells show enhanced cytotoxicity, and Gpr132 -/- mice have more mature NK cells with stronger anti-melanoma capabilities, revealing its role as a potential immune checkpoint [4].

In conclusion, Gpr132 is essential in processes such as immune cell function, tumor-macrophage crosstalk, and metabolic regulation. KO mouse models have been key in uncovering its role in diseases like breast cancer, diabetes, and in the context of NK cell-mediated anti-tumor immunity, providing insights into potential therapeutic targets for these diseases.

References:

1. Chen, Peiwen, Zuo, Hao, Xiong, Hu, Siegwart, Daniel J, Wan, Yihong. 2017. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. In Proceedings of the National Academy of Sciences of the United States of America, 114, 580-585. doi:10.1073/pnas.1614035114. https://pubmed.ncbi.nlm.nih.gov/28049847/

2. Wang, Jia-Le, Dou, Xiao-Dong, Cheng, Jie, Jiao, Ning, Yu, Xiao. 2023. Functional screening and rational design of compounds targeting GPR132 to treat diabetes. In Nature metabolism, 5, 1726-1746. doi:10.1038/s42255-023-00899-4. https://pubmed.ncbi.nlm.nih.gov/37770763/

3. Sisignano, Marco, Fischer, Michael J M, Geisslinger, Gerd. 2021. Proton-Sensing GPCRs in Health and Disease. In Cells, 10, . doi:10.3390/cells10082050. https://pubmed.ncbi.nlm.nih.gov/34440817/

4. Hui, Xinhui, Xue, Min, Ren, Yaojun, Duan, Yixin, Jiang, Wenzheng. 2025. GPR132 regulates the function of NK cells through the Gαs/CSK/ZAP70/NF-κB signaling pathway as a potential immune checkpoint. In Science advances, 11, eadr9395. doi:10.1126/sciadv.adr9395. https://pubmed.ncbi.nlm.nih.gov/40043109/

5. Foster, James R, Ueno, Shohta, Chen, Mao Xiang, Irving, Andrew J, Brown, Andrew J. 2019. N-Palmitoylglycine and other N-acylamides activate the lipid receptor G2A/GPR132. In Pharmacology research & perspectives, 7, e00542. doi:10.1002/prp2.542. https://pubmed.ncbi.nlm.nih.gov/31768260/