Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A.
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.
Obinata
Hideru
H
Department of Molecular Biochemistry, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Hattori
Tomoyasu
T
Nakane
Shinji
S
Tatei
Kazuaki
K
Izumi
Takashi
T
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005434:Flow Cytometry; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D015870:Gene Expression; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney; D044243:Linoleic Acids, Conjugated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism; D011492:Protein Hydrolysates; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D014162:Transfection
D018797:Cell Cycle Proteins; D005230:Fatty Acids, Nonesterified; C115270:G2A receptor; D007295:Inositol Phosphates; D044243:Linoleic Acids, Conjugated; D010713:Phosphatidylcholines; D011492:Protein Hydrolysates; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C007978:hydrolysin; C024347:9-hydroxy-10,12-octadecadienoic acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D048670:MAP Kinase Kinase 4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium