Gpr65, a G-protein coupled receptor, functions as a proton-sensing receptor. It is involved in multiple signaling pathways such as the Gαq-Ca2+-JNK/NF-κB, cAMP-PKA-C-Raf-ERK1/2-LKB1, and cAMP/PKA/CREB pathways, playing important roles in various biological processes like inflammation, immune response, and cell-cell communication [1,2,4]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been crucial for studying its functions.

In KO mouse models, Gpr65 deficiency significantly alleviated liver inflammation, injury, and fibrosis induced by bile duct ligation or carbon tetrachloride treatment, indicating its role in promoting liver fibrosis via activation of hepatic stellate cells and damage to hepatocytes through cytokine regulation [1]. Conditional knockout of Gpr65 in CD4+ T cells ameliorated colitis in mice, suggesting it promotes Th1 and Th17 cell-mediated gut inflammation [2]. In mice with IEC-specific deletion of Gpr65, there was dysbiosis, disrupted epithelial antimicrobial responses, and increased susceptibility to colitis, highlighting its role in maintaining intestinal mucosal homeostasis [3].

In conclusion, Gpr65 is a key regulator in inflammation, fibrosis, and immune-related processes. The KO and CKO mouse models have revealed its significance in liver fibrosis, gut inflammation, and intestinal mucosal homeostasis, providing potential therapeutic targets for diseases such as liver fibrosis and inflammatory bowel disease.

References:

1. Zhang, Kun, Zhang, Meng-Xia, Meng, Xiao-Xiang, Han, Tao, Hong, Wei. 2023. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways. In Military Medical Research, 10, 56. doi:10.1186/s40779-023-00494-4. https://pubmed.ncbi.nlm.nih.gov/38001521/

2. Lin, Ritian, Wu, Wei, Chen, Huimin, Sun, Mingming, Liu, Zhanju. . GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2. In Clinical and translational medicine, 12, e771. doi:10.1002/ctm2.771. https://pubmed.ncbi.nlm.nih.gov/35343079/

3. Li, Gengfeng, Lin, Jian, Gao, Xiang, Fang, Leilei, Liu, Zhanju. 2023. Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease. In Gut microbes, 15, 2257269. doi:10.1080/19490976.2023.2257269. https://pubmed.ncbi.nlm.nih.gov/37749885/

4. Yan, Chaolong, Yang, Zijiang, Chen, Pin, Huang, Wei, Zhang, Xiaobiao. 2024. GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression. In Journal of experimental & clinical cancer research : CR, 43, 105. doi:10.1186/s13046-024-03025-8. https://pubmed.ncbi.nlm.nih.gov/38576043/