D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia

Previous studies have shown D2-like dopamine receptor involvement in the re gulation of phospholipid methylation (PLM), while others have documented im paired methionine and folate metabolism in schizophrenia. Utilizing [C-14]f ormate labeling in cultured neuroblastoma cell lines, we now show that D4 d opamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagoni sts and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PL M was dependent upon the activity of methionine cycle enzymes, but DA faile d to increase PLM in [H-3]methionine labeling studies, indicating that a me thionine residue in the D4R might be involved in mediating PLM. A direct ro le for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-di rected mutagenesis and GTP-binding results. A comparison of PLM in lymphocy tes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechani sm by which the D4R can regulate membrane composition. Abnormalities in D4R -mediated PLM may be important in psychiatric illnesses such as schizophren ia.