Ludwig Marie-Gabrielle, Vanek Miroslava, Guerini Danilo, Gasser Jürg A, Jones Carol E, Junker Uwe, Hofstetter Hans, Wolf Romain M, Seuwen Klaus
Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.
Nature. 2003 Sep 4;425(6953):93-8. doi: 10.1038/nature01905.
Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. 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 sphingosylphosphorylcholine, 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 range, 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.
血液pH值主要通过呼吸调节和肾脏排酸维持在7.4左右的狭窄范围内。pH值稳态所涉及的分子机制尚未完全明了。在此我们表明，卵巢癌G蛋白偶联受体1（OGR1），先前被描述为鞘氨醇磷酸胆碱的受体，作为一种质子感应受体刺激肌醇磷酸的形成。该受体在pH 7.8时无活性，在pH 6.8时完全激活——定点诱变表明细胞外表面的组氨酸参与pH感应。我们发现，OGR1的近亲GPR4也对pH变化有反应，但引发环磷酸腺苷的形成。已知骨骼作为一个缓冲器官参与pH值稳态，并且成骨细胞对生理范围内的pH变化有反应，但此前这些细胞中的pH感应机制尚不清楚。我们检测到骨肉瘤细胞和原代人成骨细胞前体中OGR1的表达，并表明这些细胞表现出强烈的pH依赖性肌醇磷酸形成。对大鼠组织切片的免疫组织化学证实了成骨细胞和骨细胞中存在OGR1。我们提出，OGR1和GPR4是参与pH值稳态的质子感应受体。
