The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. We report that the G protein–coupled receptor GPR35 interacted with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca²⁺ to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). In contrast, a common T108M polymorphism in GPR35 was hypermorphic and had the opposite effects to Gpr35 deletion on Src activation and metabolic activity. The T108M polymorphism is associated with ulcerative colitis and primary sclerosing cholangitis, inflammatory diseases with a high cancer risk. GPR35 promoted homeostatic IEC turnover, whereas Gpr35 deletion or inhibition by a selective pepducin prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Thus, GPR35 acts as a central signaling and metabolic pacesetter, which reveals an unexpected role of Na/K-ATPase in macrophage and IEC biology.

钠钾泵（Na / K-ATPase）通过能量依赖性过程确保细胞的电化学梯度，该过程消耗约三分之一的再生ATP。我们报告说，G蛋白偶联受体GPR35与Na / K-ATPaseα链相互作用，并以不依赖配体的方式促进其离子转运和Src信号传导活性。删除Gpr35可增加基线Ca ²⁺达到最大水平并降低巨噬细胞和肠上皮细胞（IEC）中的Src活化和总体代谢活性。相反，GPR35中常见的T108M多态性是高态的，并且与Gpr35缺失对Src激活和代谢活性具有相反的作用。T108M多态性与溃疡性结肠炎和原发性硬化性胆管炎有关，这是具有高癌症风险的炎症性疾病。GPR35促进稳态的IEC转换，而Gpr35的缺失或选择性pepducin的抑制作用可防止小鼠炎症相关和自发性肠道肿瘤发生。因此，GPR35充当了中央信号传导和新陈代谢的指示者，揭示了Na / K-ATPase在巨噬细胞和IEC生物学中的出乎意料的作用。