Gpr68, also known as ovarian cancer G protein-coupled receptor 1 (OGR1), is a proton-sensing G-protein-coupled receptor (GPCR). It responds to extracellular acidity and is involved in multiple physiological functions. It has been implicated in regulating various cellular processes through associated pathways, and its study via genetic models like knockout mice is crucial for understanding its biological importance [3].

In vascular physiology, Gpr68-deficient mice display impaired acute flow-mediated dilation (FMD) and chronic flow-mediated outward remodeling in mesenteric arterioles, indicating it is an essential flow sensor in arteriolar endothelium [1]. In glioblastoma, inhibition of Gpr68 using a small molecule inhibitor (OGM) and genetic means leads to robust cell death in glioblastoma cell lines, suggesting Gpr68 is a critical sensor for an autocrine pro-tumorigenic signaling cascade triggered by extracellular acidification [2,5]. In oral dysplasia, GPR68-deficiency worsens the severity of chemical-induced oral dysplasia, suggesting a protective role for this gene in tumorigenesis [4]. In cerebral ischemia-reperfusion injury, GPR68 agonist treatment may inhibit the activation of the NF-κB/Hif-1α pathway, reducing oxidative and inflammatory responses [6]. In hippocampal function, GPR68 -/- mice show reduced long-term potentiation (LTP) and altered passive avoidance behavior [8]. In colonic inflammation, Ogr1-deficient (Ogr1 is another name for Gpr68) mice have decreased inflammation in certain models [7].

In conclusion, Gpr68 plays diverse and essential biological functions. Gene knockout mouse models have revealed its significance in areas such as vascular function, cancer (glioblastoma and oral dysplasia), cerebral ischemia-reperfusion injury, hippocampal function, and colonic inflammation. These findings provide insights into potential therapeutic targets for related diseases.

References:

1. Xu, Jie, Mathur, Jayanti, Vessières, Emilie, Henrion, Daniel, Patapoutian, Ardem. . GPR68 Senses Flow and Is Essential for Vascular Physiology. In Cell, 173, 762-775.e16. doi:10.1016/j.cell.2018.03.076. https://pubmed.ncbi.nlm.nih.gov/29677517/

2. Williams, Charles H, Neitzel, Leif R, Cornell, Jessica, Bar, Eli E, Hong, Charles C. 2024. GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment. In Experimental hematology & oncology, 13, 13. doi:10.1186/s40164-023-00468-1. https://pubmed.ncbi.nlm.nih.gov/38291540/

3. Wiley, Shu Z, Sriram, Krishna, Salmerón, Cristina, Insel, Paul A. 2019. GPR68: An Emerging Drug Target in Cancer. In International journal of molecular sciences, 20, . doi:10.3390/ijms20030559. https://pubmed.ncbi.nlm.nih.gov/30696114/

4. Shore, David, Griggs, Nosakhere, Graffeo, Vincent, Xu, Yan, McAleer, Jeremy P. 2023. GPR68 limits the severity of chemical-induced oral epithelial dysplasia. In Scientific reports, 13, 353. doi:10.1038/s41598-023-27546-y. https://pubmed.ncbi.nlm.nih.gov/36611126/

5. Neitzel, Leif R, Fuller, Daniela T, Williams, Charles H, Hong, Charles C. 2024. Inhibition of GPR68 kills glioblastoma in zebrafish xenograft models. In BMC research notes, 17, 235. doi:10.1186/s13104-024-06900-x. https://pubmed.ncbi.nlm.nih.gov/39180089/

6. Li, Xianglong, Xia, Kaiguo, Zhong, Chuanhong, Chen, Ligang, You, Jian. 2024. Neuroprotective effects of GPR68 against cerebral ischemia-reperfusion injury via the NF-κB/Hif-1α pathway. In Brain research bulletin, 216, 111050. doi:10.1016/j.brainresbull.2024.111050. https://pubmed.ncbi.nlm.nih.gov/39147243/

7. Perren, Leonie, Busch, Moana, Schuler, Cordelia, Hausmann, Martin, Rogler, Gerhard. 2023. OGR1 (GPR68) and TDAG8 (GPR65) Have Antagonistic Effects in Models of Colonic Inflammation. In International journal of molecular sciences, 24, . doi:10.3390/ijms241914855. https://pubmed.ncbi.nlm.nih.gov/37834303/

8. Xu, Yuanyuan, Lin, Mike T, Zha, Xiang-Ming. 2020. GPR68 deletion impairs hippocampal long-term potentiation and passive avoidance behavior. In Molecular brain, 13, 132. doi:10.1186/s13041-020-00672-8. https://pubmed.ncbi.nlm.nih.gov/32993733/