Methylmercury decreases NGF-induced TrkA autophosphorylation and neurite outgrowth in PC12 cells - PubMed

Methylmercury decreases NGF-induced TrkA autophosphorylation and neurite outgrowth in PC12 cells

Damani K Parran et al. Brain Res Dev Brain Res. 2003.

Abstract

Neurotrophin signaling through Trk receptors is important for differentiation and survival in the developing nervous system. The present study examined the effects of CH(3)Hg on (125)I-nerve growth factor (NGF) binding to the TrkA receptor, NGF-induced activation of the TrkA receptor, and neurite outgrowth in an in vitro model of differentiation using PC12 cells. Whole-cell binding assays using (125)I-NGF revealed a single binding site with a K(d) of approximately 1 nM. Methylmercury (CH(3)Hg) at 30 nM (EC(50) for neurite outgrowth inhibition) did not affect NGF binding to TrkA. TrkA autophosphorylation was measured by immunoblotting with a phospho-specific antibody. TrkA autophosphorylation peaked between 2.5 and 5 min of exposure and then decreased but was still detectable at 60 min. Concurrent exposure to CH(3)Hg and NGF for 2.5 min resulted in a concentration-dependent decrease in TrkA autophosphorylation, which was significant at 100 nM CH(3)Hg. To determine whether the observed inhibition of TrkA was sufficient to alter cell differentiation, NGF-stimulated neurite outgrowth was examined in PC12 cells after exposure to 30 nM CH(3)Hg, a concentration that inhibited TrkA autophosphorylation by approximately 50%. For comparison, a separate group of PC12 cells were exposed to a concentration of the selective Trk inhibitor K252a (30 nM), which had been shown to produce significant inhibition of TrkA autophosphorylation. Twenty-four hour exposure to either CH(3)Hg or K252a reduced neurite outgrowth to a similar degree. Our results suggest that CH(3)Hg may inhibit differentiation of PC12 cells by interfering with NGF-stimulated TrkA autophosphorylation.

Similar articles

• Effects of prolonged exposure to nanomolar concentrations of methylmercury on voltage-sensitive sodium and calcium currents in PC12 cells.

  Shafer TJ, Meacham CA, Barone S Jr. Shafer TJ, et al. Brain Res Dev Brain Res. 2002 Jun 30;136(2):151-64. doi: 10.1016/s0165-3806(02)00360-7. Brain Res Dev Brain Res. 2002. PMID: 12101032

• Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum.

  Fujimura M, Usuki F, Cheng J, Zhao W. Fujimura M, et al. Toxicol Appl Pharmacol. 2016 May 1;298:1-8. doi: 10.1016/j.taap.2016.03.002. Epub 2016 Mar 7. Toxicol Appl Pharmacol. 2016. PMID: 26965727

• Methylmercury inhibits TrkA signaling through the ERK1/2 cascade after NGF stimulation of PC12 cells.

  Parran DK, Barone S Jr, Mundy WR. Parran DK, et al. Brain Res Dev Brain Res. 2004 Mar 22;149(1):53-61. doi: 10.1016/j.devbrainres.2003.10.017. Brain Res Dev Brain Res. 2004. PMID: 15013629

• Transcriptional down-regulation of epidermal growth factor (EGF) receptors by nerve growth factor (NGF) in PC12 cells.

  Cohen G, Ettinger K, Lecht S, Lelkes PI, Lazarovici P. Cohen G, et al. J Mol Neurosci. 2014 Nov;54(3):574-85. doi: 10.1007/s12031-014-0388-2. Epub 2014 Jul 31. J Mol Neurosci. 2014. PMID: 25078264 Review.

• Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player.

  Uren RT, Turnley AM. Uren RT, et al. Front Mol Neurosci. 2014 May 14;7:39. doi: 10.3389/fnmol.2014.00039. eCollection 2014. Front Mol Neurosci. 2014. PMID: 24860421 Free PMC article. Review.

Cited by

• Environmental epigenetics in metal exposure.

  Martinez-Zamudio R, Ha HC. Martinez-Zamudio R, et al. Epigenetics. 2011 Jul;6(7):820-7. doi: 10.4161/epi.6.7.16250. Epub 2011 Jul 1. Epigenetics. 2011. PMID: 21610324 Free PMC article. Review.

• Methylmercury and nutrition: adult effects of fetal exposure in experimental models.

  Newland MC, Paletz EM, Reed MN. Newland MC, et al. Neurotoxicology. 2008 Sep;29(5):783-801. doi: 10.1016/j.neuro.2008.06.007. Epub 2008 Jul 5. Neurotoxicology. 2008. PMID: 18652843 Free PMC article. Review.

• Impact of environmental neurotoxic: current methods and usefulness of human stem cells.

  Rosca A, Coronel R, Moreno M, González R, Oniga A, Martín A, López V, González MDC, Liste I. Rosca A, et al. Heliyon. 2020 Dec 19;6(12):e05773. doi: 10.1016/j.heliyon.2020.e05773. eCollection 2020 Dec. Heliyon. 2020. PMID: 33376823 Free PMC article. Review.

• Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine, and divalent nickel.

  Slotkin TA, MacKillop EA, Ryde IT, Tate CA, Seidler FJ. Slotkin TA, et al. Environ Health Perspect. 2007 Jan;115(1):93-101. doi: 10.1289/ehp.9527. Environ Health Perspect. 2007. PMID: 17366826 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database