GPR35 prevents osmotic stress induced cell damage.

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.