Proton-sensing G-protein-coupled receptors

Marie-Gabrielle Ludwig, Miroslava Vanek, Danilo Guerini, Jürg A. Gasser, Carol E. Jones, Uwe Junker, Hans Hofstetter, Romain M. Wolf and Klaus Seuwen ()
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Marie-Gabrielle Ludwig: Novartis Institutes for Biomedical Research
Miroslava Vanek: Novartis Institutes for Biomedical Research
Danilo Guerini: Novartis Institutes for Biomedical Research
Jürg A. Gasser: Novartis Institutes for Biomedical Research
Carol E. Jones: Novartis Horsham Research Centre
Uwe Junker: Novartis Institutes for Biomedical Research
Hans Hofstetter: Novartis Institutes for Biomedical Research
Romain M. Wolf: Novartis Institutes for Biomedical Research
Klaus Seuwen: Novartis Institutes for Biomedical Research

Nature, 2003, vol. 425, issue 6953, 93-98

Abstract: Abstract Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion1,2. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine3, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8—site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range4, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.

Date: 2003
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DOI: 10.1038/nature01905

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