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.

The split promoter sequences of a tRNALeuCUG gene of Xenopus laevis have been mapped to nucleotides 13-20 and 51-64 of the tRNALeu coding sequences. The sequences closely coincide with two conserved sequence blocks present in all eukaryotic tRNA genes. The two conserved sequence blocks were found to be exchangeable between tRNA genes as chimaeric tRNAMet--tRNALeu genes proved transcriptionally active. Furthermore, two prokaryotic tRNA genes exhibiting strong homologies with the two blocks yielded specific transcripts when tested in an eukaryotic transcriptional system.

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