Significance Gpr116 is an adhesion G protein-coupled receptor (aGPCR) that is highly expressed in the kidney. Here, we report that Gpr116 localizes to A-intercalated cells in the murine collecting duct, where it functions as a significant and critical regulator of renal acid secretion by regulating the surface expression of V-ATPase proton pumps. Kidney-specific Gpr116 knockout mice develop a unique acid-base disorder, “renal tubular alkalosis,” characterized by acidic urine and alkaline blood. These findings have significant implications for other tissues with Gpr116 expression, as well as other acid-secreting epithelia. Furthermore, we propose that Gpr116 may more generally regulate endocytosis, a function that would have wide-ranging implications for both Gpr116 function and for our understanding of aGPCRs.