Signaling Actions of Electrophiles: Anti-inflammatory Therapeutic Candidates

Modulation of cellular signaling mechanisms by electrophiles. Electophiles (E) can act at many loci within the cell. A. At the cellular membrane, electrophiles can modulate ion channel activity (e.g., adduction to essential cysteine residues of the TRP channel, thereby activating TRP signaling). Some adducts can be sequestered by reaction with glutathione (GSH), and GS-electrophile adducts can undergo further thiol exchange reactions or exit the cell via a multidrug resistant protein (MDR) mechanism. B. Cytosolic proteins can react with electrophiles, inducing changes in protein structure, activity, subcellular localization, or stability. An example of these outcomes is the modulation of protein kinase signaling by electrophiles and subsequent modulation of protein activity or gene regulation (see panel C). Electrophiles also affect signaling by influencing mitochondrial respiration and redox status, for example by reacting with cytochrome c. C. In the nucleus, transcription factors can react with electrophiles to affect the transcription of genes involved in cell survival, metabolism, and differentiation. During severe oxidative conditions, electrophiles can also form adducts with DNA and promote miscoding.