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Elucidating the Physiological Role of Gprc5c, a Novel Orphan GPCR in the Kidney

Kidneys play a key role in maintaining systemic homeostasis by precisely regulating a wide variety of physiological substances in both the plasma and forming urine. To aid in this process, sensory G‐protein coupled receptors (GPCRs) act as specialized chemosensors to detect metabolites that often are effective 'signals' of abnormalities in essential physiological processes and metabolic pathways. Using a real‐time PCR screen, we previously identified several novel GPCRs that are expressed at high levels in murine whole kidney, but have not been previously examined in the kidney. In this study, we aim to uncover the functional role of Gprc5c, which we found to be highly expressed in the kidney (at a comparable level to the well‐studied and highly expressed Angiotensin receptor, AT1a; ΔCtAT1a: 6.25±0.24; ΔCtGprc5c: 7.0±0.16). Using immunohistochemistry, we found that Gprc5c is localized apically in the renal proximal tubules of wild‐type (WT) mice; this stain was absent in Gprc5c knockout (KO) mice. Because Gprc5c is an orphan receptor with no known ligand, we utilized an in vitro approach to screen potential ligands using a ligand‐induced GPCR internalization assay in transiently transfected HEK293T cells. We found that pH triggered Gprc5c activation and that the internalization is maximal in the alkaline range (pH>7.4). This pH range specifically induced internalization of Gprc5c, but not other transiently transfected GPCRs which served as controls. In addition, preliminary studies indicate that the plasma pH of Gprc5c knockout mice trends acidic compared to wild‐type littermates (KO: 7.17±0.09, n=5; WT: 7.45±0.08, n=3, p=0.07). Together, these results indicate that Gprc5c may act in the renal proximal tubule to aid in the regulation of acid‐base balance.