Abstract
G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages. G2A can be induced by diverse stimuli to cause cell cycle arrest in the G(2)/M phase in pro-B and T cells. G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis. Recently, G2A was discovered to possess proton-sensing ability. In this paper, we report another function of G2A, that is, as a receptor for 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized free fatty acids. G2A, expressed in CHO-K1 or HEK293 cells, showed 9-HODE-induced intracellular calcium mobilization, inositol phosphate accumulation, inhibition of cAMP accumulation, [(35)S]guanosine 5'-3-O-(thio)triphosphate binding, and MAP kinase activation. Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE. Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A(2) also evoked intracellular calcium mobilization in G2A-expressing cells. These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate. Thus, G2A might have a biological role in diverse pathological conditions including atherosclerosis.
Highlights
G2A was initially identified as an orphan receptor, Kabarowski et al [4] once reported that lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC) were potent ligands for G2A
During the course of a de-orphaning project of some orphan GPCRs, we found that G2A expressed in mammalian cells responded to some oxidized free fatty acids, such as 9-hydroxyoctadecadienoic acid (HODE). 9-HODE is an oxidized derivative of linoleic acid and one of the major lipid components of oxidized low-density lipoproteins (LDLs)
We demonstrate that 9-HODE causes G2A activation resulting in intracellular calcium mobilization, [35S]GTP␥S binding, inhibition of cAMP formation, and MAP kinase activation. 9-HODE in its free fatty acid form, but not in the form incorporated in phosphatidylcholine (PC) or cholesteryl ester, is effective in activating G2A
Summary
G2A was initially identified as an orphan receptor, Kabarowski et al [4] once reported that lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC) were potent ligands for G2A. We demonstrate that 9-HODE causes G2A activation resulting in intracellular calcium mobilization, [35S]GTP␥S binding, inhibition of cAMP formation, and MAP kinase activation. 9(S)-HODE evoked intracellular calcium mobilization in CHO-G2A cells in a dose-dependent manner.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
