Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

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.

Nitro-fatty Acid Reaction with Glutathione and Cysteine

“…Fatty acid-derived electrophiles also serve as ligands for receptors activated by the modulation of a critical Cys; for * This work was supported in part by National Institutes of Health Grants example, 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ) binds to peroxisome proliferator-activated receptor-␥ (PPAR␥), increasing transcription of PPAR response element-regulated genes (17)(18)(19). Of note, electrophiles also modulate the activities of nervous system targets such as synaptic proteins (20) and the excitatory ion channel, TRPA1 (21,22) by alkylating critical thiols. This mode of signal transduction is distinct from more traditional non-covalent ligand-receptor interactions that elicit responses by inducing conformational changes.…”

Acrylamide alters neurotransmitter induced calcium responses in murine ESC-derived and primary neurons

“…SH of cysteine) in synaptic compartments (LoPachin and Gavin, 2012). This interaction is well documented for NO (LoPachin and Barber, 2006). Therefore, ACR may, similarly to the physiological NO, also bind to cysteine residues (e.g.…”

Covalent Protein Adduction by Drugs of Abuse

“…55,56 Variability in amino acid reactivity can be exemplified by nucleophilic lysine and cysteine residues. Nucleophilic reactivity of both residues is mediated by their ionization state.…”

“…However, the occurrence of catalytic diads can significantly modify cysteine pK a values, promoting thiolate formation. 56 Catalytic diads are cysteine residues adjacent to basic residues (i.e., lysine, histidine, arginine) that facilitate in the formation of thiolates from cysteine sulfhydryls. Figure 9 shows the influence of adjacent basic residues in forming thiolate ions from cysteine sulfhydryl moieties.…”