Synaptic cysteine sulfhydryl groups as targets of electrophilic neurotoxicants

Richard M. LoPachin, David S. Barber

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Many structurally diverse chemicals (e.g., acrylamide, 2,4-dithiobiuret, methylmercury) are electrophiles and cause synaptic dysfunction by unknown mechanisms. The purpose of this Forum review is to discuss the possibility that highly nucleophilic cysteine thiolate groups within catalytic triads of synaptic proteins represent specific and necessary targets for electrophilic neurotoxicants. Most of these toxicants share the ability to adduct or otherwise modify nucleophilic sulfhydryl groups. It is also now recognized that synaptic activity is regulated by the redox state of certain cysteine sulfhydryl groups on proteins. Electrophilic neurotoxicants might, therefore, produce synaptic toxicity by modifying these thiols. Because most proteins contain cysteine residues, target specificity is an issue that significantly detracts from the mechanistic validity of this hypothesis. However, recent research indicates that these thiolates are receptors for the endogenous nitric oxide (NO) pathway and that subsequent reversible S-nitrosylation finely regulates a broad spectrum of synaptic activities. We hypothesize that electrophilic neurotoxicants selectively adduct/derivatize NO-receptor thiolates in catalytic triads and that the resulting loss of fine gain control impairs neurotransmission and produces neurotoxicity. This proposal has mechanistic implications for a large class of electrophilic chemicals used in the agricultural and industrial sectors. In addition, research based on this hypothesis could provide mechanistic insight into neurodegenerative conditions such as Parkinsonism and Alzheimer's disease that presumably involve endogenous production of neurotoxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal). The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes.

Original languageEnglish (US)
Pages (from-to)240-255
Number of pages16
JournalToxicological Sciences
Volume94
Issue number2
DOIs
StatePublished - Dec 2006

Fingerprint

Cysteine
Nitric Oxide
Research
Acrolein
Proteins
Aptitude
Acrylamide
Gain control
Parkinsonian Disorders
Sulfhydryl Compounds
Synaptic Transmission
Oxidation-Reduction
Toxicity
Alzheimer Disease
Soluble Guanylyl Cyclase
4-hydroxy-2-nonenal
2,4-dithiobiuret
cysteine thiolate

Keywords

  • Neurotoxicity
  • Nitric oxide
  • Protein adduct
  • Redox signaling
  • S-nitrosylation
  • Toxic neuropathy

ASJC Scopus subject areas

  • Toxicology

Cite this

Synaptic cysteine sulfhydryl groups as targets of electrophilic neurotoxicants. / LoPachin, Richard M.; Barber, David S.

In: Toxicological Sciences, Vol. 94, No. 2, 12.2006, p. 240-255.

Research output: Contribution to journalArticle

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