Novel roles of GPCRs in the renal collecting duct

GPCRs serve to coordinate renal collecting duct function, orchestrating fine-tuned regulation of water, electrolyte, and acid-base homeostasis. Classical GPCRs such as the vasopressin V2 receptor (V2R) have well-established roles: the V2R serves to regulate water reabsorption, and V2R dysregulation can underly diabetes insipidus. However, transcriptomic and phosphoproteomic advances have revealed a diverse repertoire of understudied GPCRs expressed in the collecting duct whose physiological roles remain largely undefined. Here, we review emerging insights into three such receptors-GPR39, ADGRF5, and ADGRG3-highlighting their distinct contributions to collecting duct function. We also discuss atypical GPCR-related signaling, including PKD1 and MAGED2, which expand the conceptual framework of GPCR biology in renal function. Collectively, these findings illustrate that GPCRs play diverse and underappreciated roles in collecting duct physiology and pathophysiology, and that continued mechanistic studies may uncover new therapeutic opportunities for kidney disease.