Elias Joshua E, Debela Mekdes, Sewell Gavin W, Stopforth Richard J, Partl Hannah, Heissbauer Sophie, Holland Lorraine M, Karlsen Tom H, Kaser Arthur, Kaneider Nicole C
Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, CB2 0AW, UK.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
Commun Biol. 2025 Mar 22;8(1):478. doi: 10.1038/s42003-025-07848-9.
GPR35 is an orphan G-protein coupled receptor that has been implicated in the development of cancer. GPR35 regulates the Na/K-ATPase's pump and signalling function. Here we show GPR35's critical role in ion flux that in turn controls cellular osmotic pressure and Na-dependent transport in HepG2 and SW480 cells. GPR35 deficiency results in increased levels of intracellular Na, osmotic stress and changes in osmolytes leading to increased cells size and decreased glutamine import in vitro and in vivo. The GPR35-T108M risk variant, which increases risk for primary sclerosing cholangitis and inflammatory bowel disease, leads to lower intracellular Na levels, and enhanced glutamine uptake. High salt diet (HSD) in wildtype mice resembles the intestinal epithelial phenotype of their Gpr35 littermates with decreased Goblet cell size and numbers. This indicates that GPR35's regulation of the Na/K-ATPase controls ion homeostasis, osmosis and Na-dependent transporters.
GPR35是一种孤儿G蛋白偶联受体，与癌症的发生发展有关。GPR35调节钠钾ATP酶的泵功能和信号传导功能。在此我们展示了GPR35在离子通量中的关键作用，而离子通量反过来又控制HepG2和SW480细胞中的细胞渗透压和钠依赖性转运。GPR35缺乏导致细胞内钠水平升高、渗透压应激以及渗透溶质的变化，从而导致体外和体内细胞大小增加以及谷氨酰胺摄取减少。GPR35 - T108M风险变体增加了原发性硬化性胆管炎和炎症性肠病的风险，导致细胞内钠水平降低，并增强谷氨酰胺摄取。野生型小鼠的高盐饮食（HSD）类似于其Gpr35同窝小鼠的肠道上皮表型，杯状细胞大小和数量减少。这表明GPR35对钠钾ATP酶的调节控制着离子稳态、渗透作用和钠依赖性转运蛋白。
