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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleTOXICOLOGY

Methylisothiazolinone, A Neurotoxic Biocide, Disrupts the Association of Src Family Tyrosine Kinases with Focal Adhesion Kinase in Developing Cortical Neurons

Kai He, Jason Huang, Carl F. Lagenaur and Elias Aizenman
Journal of Pharmacology and Experimental Therapeutics June 2006, 317 (3) 1320-1329; DOI: https://doi.org/10.1124/jpet.106.103044
Kai He
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Jason Huang
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Carl F. Lagenaur
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Elias Aizenman
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Abstract

Methylisothiazolinone (MIT) is a biocide widely used in industrial and cosmetic products with potential as a neurotoxicant. We previously reported that short acute exposures to relatively high concentrations of MIT (100 μM) lead to widespread and selective neuronal death in vitro. To evaluate the biological properties of chronic exposures to MIT, freshly dissociated rat cortical neurons were continuously exposed to low concentrations (0.1–3 μM) of the biocide in serum-containing media. Although we observed minimal effects on cell viability, MIT induced a dramatic inhibition of neurite outgrowth. Immunoblotting and immunoprecipitation experiments revealed that focal adhesion kinase (FAK) phosphorylation was primarily affected by the MIT treatment. The phosphorylation level at tyrosines 576 and 861 of FAK was significantly decreased and likely contributed to the overall reduction of tyrosine phosphorylation of this protein. MIT inhibited Src family kinases (SFKs) in cell-free assays and led to the physical dissociation of FAK from the signaling complexes that it normally forms with c-Src and Fyn in developing neurons. High-density neuronal cultures were then employed to increase cell-to-cell contact. This approach resulted in an overall enhancement of SFKs and FAK phosphorylation and could overcome the deficits induced by MIT. This study suggests that a disruption of FAK-SFK complexes due to SFK inhibition leads to FAK dysfunction, with detrimental effects to immature neurons. Prolonged exposure to low levels of MIT and related compounds may have damaging consequences to the developing nervous system.

Footnotes

  • This work was supported in part by the Pittsburgh Institute for Neurodegenerative Disorders.

  • doi:10.1124/jpet.106.103044.

  • ABBREVIATIONS: CMIT, 5-chloro-2-methyl-4-isothiazolin-3-one; MIT, 2-methyl-4-isothiazolin-3-one; ERK, extracellular signal-regulated kinase; SFK, Src family kinase; FAK, focal adhesion kinase; PYK2, proline-rich tyrosine kinase 2; PD98059, 2′-amino-3′-methoxyflavone; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; PLL, poly-l-lysine; PBS, phosphate-buffered saline; LDH, lactate dehydrogenase; PAGE, polyacrylamide gel electrophoresis; PBST, PBS with 0.05% Tween 20; ANOVA, analysis of variance; NCAM, neural cell adhesion molecule.

    • Received February 16, 2006.
    • Accepted March 16, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleTOXICOLOGY

Methylisothiazolinone, A Neurotoxic Biocide, Disrupts the Association of Src Family Tyrosine Kinases with Focal Adhesion Kinase in Developing Cortical Neurons

Kai He, Jason Huang, Carl F. Lagenaur and Elias Aizenman
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 1320-1329; DOI: https://doi.org/10.1124/jpet.106.103044

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Research ArticleTOXICOLOGY

Methylisothiazolinone, A Neurotoxic Biocide, Disrupts the Association of Src Family Tyrosine Kinases with Focal Adhesion Kinase in Developing Cortical Neurons

Kai He, Jason Huang, Carl F. Lagenaur and Elias Aizenman
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 1320-1329; DOI: https://doi.org/10.1124/jpet.106.103044
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