The diversity and near universal expression of G protein-coupled receptors (GPCR) reflects their involvement in most physiological processes. The GPCR superfamily is the largest in the human genome, and GPCRs are common pharmaceutical targets. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential. We previously identified an adhesion-class GPCR, Gpr116, as one of the most abundant GPCRs in the kidney. Here, we show that Gpr116 is highly expressed in specialized acid-secreting A-intercalated cells (A-ICs) in the kidney using both imaging and functional studies, and we demonstrate in situ receptor activation using a synthetic agonist peptide unique to Gpr116. Kidney-specific knockout (KO) of Gpr116 caused a significant reduction in urine pH (i.e., acidification) accompanied by an increase in blood pH and a decrease in pCO₂ compared to WT littermates. Additionally, immunogold electron microscopy shows a greater accumulation of V-ATPase proton pumps at the apical surface of A-ICs in KO mice compared to controls. Furthermore, pretreatment of split-open collecting ducts with the synthetic agonist peptide significantly inhibits proton flux in ICs. These data suggest a tonic inhibitory role for Gpr116 in the regulation of V-ATPase trafficking and urinary acidification. Thus, the absence of Gpr116 results in a primary excretion of acid in KO mouse urine, leading to mild metabolic alkalosis (“renal tubular alkalosis”). In conclusion, we have uncovered a significant role for Gpr116 in kidney physiology, which may further inform studies in other organ systems that express this GPCR, such as the lung, testes, and small intestine.

G 蛋白偶联受体 (GPCR) 的多样性和近乎普遍的表达反映了它们参与大多数生理过程。 GPCR 超家族是人类基因组中最大的，GPCR 是常见的药物靶标。因此，揭示未被充分研究的 GPCR 的功能提供了丰富的未开发的治疗潜力。我们之前鉴定出粘附类 GPCR，Gpr116，是肾脏中最丰富的 GPCR 之一。在这里，我们通过成像和功能研究表明，Gpr116 在肾脏中专门的泌酸 A 嵌入细胞 (A-IC) 中高度表达，并且我们使用 Gpr116 独特的合成激动剂肽证明了原位受体激活。与WT同窝小鼠相比，Gpr116的肾脏特异性敲除(KO)导致尿液pH值显着降低（即酸化），并伴随血液pH值升高和pCO ₂降低。此外，免疫金电子显微镜显示，与对照组相比，KO 小鼠 A-IC 顶端表面的 V-ATPase 质子泵积累更多。此外，用合成激动剂肽预处理裂开的集合管可显着抑制 IC 中的质子通量。这些数据表明 Gpr116 在调节 V-ATP 酶运输和尿液酸化中具有强效抑制作用。因此，Gpr116 的缺失导致 KO 小鼠尿液中酸的主要排泄，导致轻度代谢性碱中毒（“肾小管性碱中毒”）。总之，我们发现了 Gpr116 在肾脏生理学中的重要作用，这可能会进一步为表达该 GPCR 的其他器官系统（例如肺、睾丸和小肠）的研究提供信息。