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 regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.
Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
A
A
Sharma
M L
ML
Kramer
P F
PF
Wick
D
D
Liu
S
S
Chari
S
S
Shim
W
W
Tan
D
D
Ouellette
M
M
Nagata
C J
CJ
DuRand
M
M
Kotb
R C
RC
Deth
D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D002250:Carbon Radioisotopes; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005561:Formates / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma; D010743:Phospholipids / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011618:Psychotic Disorders / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D012457:Salicylamides / Q000494:pharmacology; D012559:Schizophrenia / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D000631:Aminopyridines; D001552:Benzazepines; D002250:Carbon Radioisotopes; C493599:DRD4 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D005561:Formates; D010743:Phospholipids; D010880:Piperidines; D011725:Pyridines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D012457:Salicylamides; D050638:Receptors, Dopamine D4; C106117:U 101958; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020891:Raclopride; D012436:S-Adenosylmethionine; D008715:Methionine; D003024:Clozapine