Immediate Communication

Molecular Psychiatry (2004) 9, 358–370. doi:10.1038/sj.mp.4001476 Published online 27 January 2004

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

M Waly1, H Olteanu2, R Banerjee2, S-W Choi3, J B Mason3, B S Parker4, S Sukumar4, S Shim1, A Sharma1, J M Benzecry1, V-A Power-Charnitsky1 and R C Deth1

  1. 1Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
  2. 2Biochemistry Department, University of Nebraska, Lincoln, NE 68588, USA
  3. 3Vitamin Metabolism Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA
  4. 4Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA

Correspondence: RC Deth, Northeastern University, 312 Mugar Hall, 360 Huntington Avenue, Boston, MA 02115, USA. E-mail: r.deth@neu.edu

Received 23 July 2003; Revised 30 October 2003; Accepted 12 November 2003; Published online 27 January 2004.

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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.

Keywords:

autism, attention deficit hyperactivity disorder, P13-kinase, D4 dopamine receptor, DNA methylation, phospholipid methylation, lead, mercury