Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Genes (Basel). 2024 Sep 1;15(9):1151. doi: 10.3390/genes15091151.
The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction and accumulation of acids (protons), the extracellular pH is characteristically more acidic in inflamed tissues and tumors in comparison to normal tissues. A family of proton-sensing G-protein-coupled receptors (GPCRs) has been identified as molecular sensors for cells responding to acidic tissue microenvironments. Herein, we review the current research progress pertaining to these proton-sensing GPCRs, including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), in inflammation and cancer. Growing evidence suggests that GPR4 and GPR68 are mainly pro-inflammatory, whereas GPR65 is primarily anti-inflammatory, in various inflammatory disorders. Both anti- and pro-tumorigenic effects have been reported for this family of receptors. Moreover, antagonists and agonists targeting proton-sensing GPCRs have been developed and evaluated in preclinical models. Further research is warranted to better understand the roles of these proton-sensing GPCRs in pathophysiology and is required in order to exploit them as potential therapeutic targets for disease treatment.
精确调节 pH 值稳态对于正常生理机能至关重要。然而，在组织微环境中，它可能会受到炎症和癌症等病理状况的影响。由于酸（质子）的过度产生和积累，与正常组织相比，炎症组织和肿瘤的细胞外 pH 值通常更偏酸性。已鉴定出一组质子感应 G 蛋白偶联受体（GPCR）作为细胞对酸性组织微环境做出反应的分子传感器。在此，我们综述了与这些质子感应 GPCR（包括 GPR4、GPR65（TDAG8）和 GPR68（OGR1））在炎症和癌症中相关的最新研究进展。越来越多的证据表明，在各种炎症性疾病中，GPR4 和 GPR68 主要是促炎的，而 GPR65 主要是抗炎的。该受体家族既有抗肿瘤作用，也有促肿瘤作用。此外，已经开发并在临床前模型中评估了针对质子感应 GPCR 的拮抗剂和激动剂。需要进一步研究以更好地了解这些质子感应 GPCR 在病理生理学中的作用，并需要将其作为疾病治疗的潜在治疗靶点加以利用。
