Activation of methionine synthase by insulin-like growth factor-1 and dopamine: A target for neurodevelopmental toxins and thimerosal

M. Waly, H. Olteanu, R. Banerjee, S. W. Choi, J. B. Mason, B. S. Parker, S. Sukumar, S. Shim, A. Sharma, J. M. Benzecry, V. A. Power-Charnitsky, R. C. Deth

Research output: Research - peer-reviewArticle

Abstract

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu2+ promoted enzyme activity and methylation, while Cu+, Pb2+, Hg2+ and Al3+ were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.

LanguageEnglish (US)
Pages358-370
Number of pages13
JournalMolecular Psychiatry
Volume9
Issue number4
DOIs
StatePublished - Apr 2004

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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Thimerosal
Somatomedins
Methylation
Dopamine
DNA Methylation
Intercellular Signaling Peptides and Proteins
Ethanol
Folic Acid
Phospholipids
Mitogen-Activated Protein Kinase Kinases
Heavy Metals
Aluminum
Mercury
Neuroblastoma
Phosphatidylinositol 3-Kinases
Metals
Ions
Gene Expression
Enzymes

Keywords

  • Attention deficit hyperactivity disorder
  • Autism
  • D4 dopamine receptor
  • DNA methylation
  • Lead
  • Mercury
  • P13-kinase
  • Phospholipid methylation

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

Cite this

Waly, M., Olteanu, H., Banerjee, R., Choi, S. W., Mason, J. B., Parker, B. S., ... Deth, R. C. (2004). Activation of methionine synthase by insulin-like growth factor-1 and dopamine: A target for neurodevelopmental toxins and thimerosal. Molecular Psychiatry, 9(4), 358-370. DOI: 10.1038/sj.mp.4001476

Activation of methionine synthase by insulin-like growth factor-1 and dopamine : A target for neurodevelopmental toxins and thimerosal. / Waly, M.; Olteanu, H.; Banerjee, R.; Choi, S. W.; Mason, J. B.; Parker, B. S.; Sukumar, S.; Shim, S.; Sharma, A.; Benzecry, J. M.; Power-Charnitsky, V. A.; Deth, R. C.

In: Molecular Psychiatry, Vol. 9, No. 4, 04.2004, p. 358-370.

Research output: Research - peer-reviewArticle

Waly, M, Olteanu, H, Banerjee, R, Choi, SW, Mason, JB, Parker, BS, Sukumar, S, Shim, S, Sharma, A, Benzecry, JM, Power-Charnitsky, VA & Deth, RC 2004, 'Activation of methionine synthase by insulin-like growth factor-1 and dopamine: A target for neurodevelopmental toxins and thimerosal' Molecular Psychiatry, vol 9, no. 4, pp. 358-370. DOI: 10.1038/sj.mp.4001476
Waly, M. ; Olteanu, H. ; Banerjee, R. ; Choi, S. W. ; Mason, J. B. ; Parker, B. S. ; Sukumar, S. ; Shim, S. ; Sharma, A. ; Benzecry, J. M. ; Power-Charnitsky, V. A. ; Deth, R. C./ Activation of methionine synthase by insulin-like growth factor-1 and dopamine : A target for neurodevelopmental toxins and thimerosal. In: Molecular Psychiatry. 2004 ; Vol. 9, No. 4. pp. 358-370
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