Feeling It in Your Bones: Sensing Acidosis

Abstract

The pH of blood, which is tightly maintained at ~pH 7.4, is primarily controlled through the regulation of acid excretion by the kidneys and carbon dioxide loss through the lungs. Additionally, the bones, which store bicarbonate, act to buffer metabolic acidosis. Osteoblasts respond to physiological changes in pH; the mechanisms whereby they sense these changes, however, remain unclear. Ludwig et al. found that cell lines (CCL39 hamster fibroblasts and HEK293 cells) transfected with ovarian cancer G protein-coupled receptor 1 (OGR1) displayed strongly pH-dependent production of inositol phosphate (IP). OGR1 is a heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) that was previously identified as a receptor for sphingosylphosphorylcholine. After transfection with OGR1, IP production was half-maximal at pH 7.48 and maximal at pH 6.8. Mutational analysis indicated that pH sensitivity depended on five extracellular histidine residues. Copper and zinc, which are coordinated by histidine pairs and would be expected to stabilize them in an unprotonated state, inhibited OGR1- and pH-dependent stimulation of IP production. A closely related receptor, GPR4 (G protein-coupled receptor 4), displayed pH-dependent production of cyclic adenosine monophosphate. The authors used reverse-transcription polymerase chain reaction (RT-PCR) to show that both a human osteosarcoma cell line and primary human preosteoblasts expressed OGR1 mRNA and immunohistochemistry to demonstrate OGR1 protein in osteoblasts and osteocytes in rat bone. Both osteosarcoma cells and preosteoblasts exhibited pH-sensitive IP production. These data suggest that OGR1 and GPR4 can act as pH sensors and that OGR1 may play a role in regulating the cell-mediated responses of bone to metabolic acidosis.M.-G. Ludwig, M. Vanek, D. Guerini, J. A. Gasser, C. E. Jones, U. Junker, H. Hofstetter, R. M. Wolf, K. Seuwen, Proton-sensing G-protein-coupled receptors. Nature 425, 93-98 (2003). [Online Journal]