Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway

Ren Zhao, Yuen Chen, Wenbo Tan, Mostafa Waly, Alok Sharma, Patrick Stover, Andre Rosowsky, Barbara Malewicz, Richard C. Deth

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17 Citations (Scopus)

Abstract

In a previous study we demonstrated the ability of dopamine (DA) to stimulate phospholipid methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Over-expression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.

Original languageEnglish
Pages (from-to)788-796
Number of pages9
JournalJournal of Neurochemistry
Volume78
Issue number4
DOIs
Publication statusPublished - 2001

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Keywords

  • 5-methyltetrahydrofolate
  • D4 dopamine receptors
  • Folic acid metabolism
  • Phospholipid methylation
  • Purine metabolism
  • Schizophrenia

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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