G2A Is a Proton-sensing G-protein-coupled Receptor Antagonized by Lysophosphatidylcholine

Abstract

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 protondependent activation of G2A.

Lysophosphatidylcholine suppresses apoptosis and induces neurite outgrowth in PC12 cells through activation of phospholipase D2

“…Furthermore, G2A is endogenously expressed in PC12 cells and activated by LPC treatment (Ikeno et al, 2005). However, several recent studies demonstrated that these receptors can be activated by extracellular proton (Bektas et al, 2003;Tomura et al, 2005), and LPC antagonizes the pH-dependent activation of G2A (Murakami et al, 2004). Therefore, involvement of G2A in LPCinduced cellular responses remains to be clarified.…”

Identification of T Cell Death-associated Gene 8 (TDAG8) as a Novel Acid Sensing G-protein-coupled Receptor

“…The identification of TDAG8 (in addition to GPR4, OGR1, and G2A) as a proton-sensing GPCR will improve our understanding of the versatile roles of extracellular pH (13,14). OGR1 and G2A stimulated inositol phosphate formation, whereas GPR4 (like TDAG8) elicited cAMP formation.…”

“…Meanwhile, GPR4 was shown to bind both sphingosylphosphorylcholine and lysophosphatidylcholine (12). However, OGR1, GPR4, and G2A were also identified as proton-sensing receptors (13,14). The relatively high level of sequence homology between TDAG8 and these three receptors therefore suggested the possibility that TDAG8 is also activated in a pH-dependent manner.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…29 Furthermore, G2A receptor signaling may also depend on other oxidized fatty acids 30 for specific interactions with intracellular G-proteins and GPCRs. 31 Thus, the effects of LPC or other lysophospholipids on migration may depend on the specific phagocyte, owing to differential expression of GPCRs and G-proteins in different cell types.…”