A Specific Histidine Residue Determines Species-Specific Sensitivity to Metal Ions in Ovarian Cancer G Protein-Coupled Receptor 1.

Mammalian ovarian cancer G protein-coupled receptor 1 (OGR1; also known as GPR68) functions as both a proton- and metal-ion-sensing receptor, activating multiple intracellular signaling pathways. Although OGR1 homologs across vertebrates are commonly activated under low pH conditions, their responsiveness to metal ions varies by species, possibly reflecting differences in physiological metal requirements. To identify the residues responsible for metal ion sensing, we analyzed human OGR1 and its homologs in zebrafish and African clawed frog. Nickel ions activated human OGR1 and one African clawed frog homolog (xLOGR1#3) but not zebrafish OGR1 and another African clawed frog homolog (xLOGR1#1), which lack a specific histidine residue in the first extracellular loop. Substituting histidine with alanine in human OGR1 reduced metal-ion-induced activation, without significantly affecting proton responsiveness. Conversely, introducing histidine at the corresponding position restored the metal ion sensitivity. This histidine-dependent activation has also been observed for cobalt and manganese ions. These findings suggest that, beyond its role as a proton sensor, OGR1 has evolved metal-ion-sensing capabilities, potentially reflecting species-specific adaptation.