G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine.
G2A (from G2 accumulation) is a G-protein-coupled receptor (GPCR) that regulates the cell cycle, proliferation, oncogenesis, and immunity. G2A shares significant homology with three GPCRs including ovarian cancer GPCR (OGR1/GPR68), GPR4, and T cell death-associated gene 8 (TDAG8). Lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC) were reported as ligands for G2A and GPR4 and for OGR1 (SPC only), and a glycosphingolipid psychosine was reported as ligand for TDAG8. As OGR1 and GPR4 were reported as proton-sensing GPCRs (Ludwig, M. G., Vanek, M., Guerini, D., Gasser, J. A., Jones, C. E., Junker, U., Hofstetter, H., Wolf, R. M., and Seuwen, K. (2003) Nature 425, 93-98), we evaluated the proton-sensing function of G2A. Transient expression of G2A caused significant activation of the zif 268 promoter and inositol phosphate (IP) accumulation at pH 7.6, and lowering extracellular pH augmented the activation only in G2A-expressing cells. LPC inhibited the pH-dependent activation of G2A in a dose-dependent manner in these assays. Thus, G2A is another proton-sensing GPCR, and LPC functions as an antagonist, not as an agonist, and regulates the proton-dependent activation of G2A.
Department of Biochemistry, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Naoka
N
Murakami
Takehiko
T
Yokomizo
Toshiaki
T
Okuno
Takao
T
Shimizu
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D005434:Flow Cytometry; D017930:Genes, Reporter; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047468:Immunoprecipitation; D007295:Inositol Phosphates / Q000737:chemistry; D008024:Ligands; D008244:Lysophosphatidylcholines / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011522:Protons; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
D000199:Actins; D018797:Cell Cycle Proteins; C115270:G2A receptor; C097350:GPR12 protein, human; C091670:GPR4 protein, human; C513334:GPR65 protein, human; C513337:GPR65 protein, mouse; D007295:Inositol Phosphates; D008024:Ligands; D008244:Lysophosphatidylcholines; D011522:Protons; D043562:Receptors, G-Protein-Coupled; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D006639:Histidine; D013110:Sphingosine