The proton-activated G protein coupled receptor OGR1 acutely regulates the activity of epithelial proton transport proteins

The Ovarian cancer G protein-coupled Receptor 1 (OGR1; GPR68) is proton-sensitive in the pH range of 6.8 - 7.8. However, its physiological function is not defined to date. OGR1 signals via inositol trisphosphate and intracellular calcium, albeit downstream events are unclear. To elucidate OGR1 function further, we transfected HEK293 cells with active OGR1 receptor or a mutant lacking 5 histidine residues (H5Phe-OGR1). An acute switch of extracellular pH from 8 to 7.1 (10 nmol/l vs 90 nmol/l protons) stimulated NHE and H(+)-ATPase activity in OGR1-transfected cells, but not in H5Phe-OGR1-transfected cells. ZnCl(2) and CuCl(2) that both inhibit OGR1 reduced the stimulatory effect. The activity was blocked by chelerythrine, whereas the ERK1/2 inhibitor PD 098059 had no inhibitory effect. OGR1 activation increased intracellular calcium in transfected HEK293 cells. We next isolated proximal tubules from kidneys of wild-type and OGR1-deficient mice and measured the effect of extracellular pH on NHE activity in vitro. Deletion of OGR1 affected the pH-dependent proton extrusion, however, in the opposite direction as expected from cell culture experiments. Upregulated expression of the pH-sensitive kinase Pyk2 in OGR1 KO mouse proximal tubule cells may compensate for the loss of OGR1. Thus, we present the first evidence that OGR1 modulates the activity of two major plasma membrane proton transport systems. OGR1 may be involved in the regulation of plasma membrane transport proteins and intra- and/or extracellular pH

The H+-Activated Ovarian Cancer G Protein-Coupled Receptor 1 (OGR1) is responsible for Renal Calcium Loss during Acidosis

ABSTRACT Hypercalciuria is a common feature during metabolic acidosis. However, the mechanisms sensing acidosis and inducing increased urinary calcium excretion during acidosis are still unknown. Here we report that mice deficient for the Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) did not excrete more calcium during chronic metabolic acidosis. Wild type (OGR1+/+) and OGR1-deficient mice (OGR1-/-) were subjected to standard chow (control) or 0.28 M NH4Cl in water for 1 day (acute metabolic acidosis) or 2 % NH4Cl in food for 7 days (chronic metabolic acidosis). OGR1 mRNA is ubiquitously expressed, including kidneys, and found along the entire nephron. No differences in responding to the acid load were observed in OGR1-/- mice, except for higher plasma [HCO3-] after 1 day. Bone mineral density and resorption activity of osteoclasts were similar between OGR1+/+ and OGR1-/- mice. Plasma PTH and Vitamin D3 levels were indistinguishable. However, the expression levels of key proteins for active transepithelial Ca2+ reabsorption in the distal convoluted tubule, TRPV5 and Calbindin-D28k were increased in OGR1-/- mice under metabolic acidosis. TRPV5 abundance was downregulated in wild type mice during metabolic acidosis but maintained at the same level in the absence of OGR1. OGR1-/- also exhibited higher NHE3 abundance when compared to OGR1+/+ under metabolic acidosis. In conclusion, OGR1 is a pH sensor involved in the hypercalciuria developed during metabolic acidosis and may regulate renal calcium excretion through modulation of proximal tubular NHE3 activity and regulation of the distal tubule TRPV5 calcium channel