D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia
D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia
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DOI：
10.1038/sj.mp.4000522
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发表时间：
1999-05-01
影响因子：
11
通讯作者：
Deth, RC
中科院分区：
文献类型：
--
作者：
Sharma, A;Kramer, ML;Deth, RC
以前的研究表明，D2样多巴胺受体参与调节磷脂甲基化（PLM），而其他人则记录了精神分裂症中蛋氨酸和叶酸代谢受损。利用[C-14]甲酸标记培养的神经母细胞瘤细胞系，我们现在表明，D4多巴胺受体（D4 R）介导的多巴胺（DA）对PLM的刺激作用。DA的作用被高度D4 R选择性拮抗剂有力地阻断，并被D4 R选择性激动剂CP-226269刺激。DA刺激的PLM依赖于蛋氨酸循环酶的活性，但DA未能增加PLM中[H-3]蛋氨酸标记的研究，表明在D4 R中的蛋氨酸残基可能参与介导PLM。从腺苷酸化、定点诱变和GTP结合结果进一步表明，MET 313位于紧邻磷脂头基的跨膜螺旋6号上，具有直接作用。精神分裂症患者与对照组淋巴细胞中PLM的比较显示，精神分裂症组的活性低四倍。这些发现揭示了D4 R可以调节膜组成的新机制。D4 R介导的PLM的缺失可能在精神疾病如精神分裂症中很重要。
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 [C-14]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 [H-3]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.