Proton-sensing G-protein-coupled receptors.
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.
Ludwig
Marie-Gabrielle
MG
Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.
Vanek
Miroslava
M
Guerini
Danilo
D
Gasser
Jürg A
JA
Jones
Carol E
CE
Junker
Uwe
U
Hofstetter
Hans
H
Wolf
Romain M
RM
Seuwen
Klaus
K
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011487:Protein Conformation; D011522:Protons; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems
C091670:GPR4 protein, human; C486281:GPR68 protein, human; C000590690:LOC102553138 protein, rat; D010716:Phosphatidylinositols; D011522:Protons; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D006639:Histidine; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins