Redox signaling

Redox signaling is when free radicals, reactive oxygen species (ROS), and other electronically activated species such as nitric oxide and other oxides of nitrogen act as biological messengers. For example, reactive oxygen species likely play a key role in fibrocyte activation and thus scar formation. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules. Similarly, modulation of charge-transfer processes and electronic conduction in macromolecules is also redox signaling. For a review, see Forman.

History
In a series of papers beginning in 1941, Szent-Gyorgyi proposed that modulation of electronic processes in semiconductive macromolecules plays a key role in biological function and in diseases such as cancer. Hush reviews the history of such molecular electronics.

Similarly, the first modern statement of the "ROS are messengers" component of redox signaling appears to be that of Proctor, who at a 1979 congress of free radical investigators further generalized the concept to suggest that " ....active oxygen metabolites act as specific intermediary transmitter substances for a variety of biological processes including inflammation, fibrosis, and possibly, neurotransmission.." and " One explanation for this data is that various active oxygen species ( or such products as hydroperoxides ) may act as specific transmitter substances....". After meeting with significant early opposition, this was finally published in a 1984 review. The next reference seems to be Bochner and coworkers. , reporting increased synthesis of "alarmome" adenylylated nucleotides as a specific response to oxidative stress in bacteria.

Electronic conduction in redox signaling
Hush credits Mcginness and coworkers. with the first experimental confirmation of Szent-Gyorgyi's theories concerning semiconductor mechanisms in cellular signaling. Priel and coworkers postulate active electronic mechanisms in modulation of cellular processes by microtubules. Bettinger and Bao review recent work on biomaterial-based organic electronic devices. Such may play s role in control of cellular function.

Reactive oxygen species as messengers
The formation of ROS such as hydrogen peroxide underlies much biotic and abiotic stress signaling. For example, as signaling molecules, hydrogen peroxide and other ROS post- translationally modify target proteins by oxidizing thiol groups, thus forming disulfide bonds that reversibly alter protein structure and function. Specificity is achieved by localized production, concatenate hormone or calcium signaling, with targeted secondary oxidation occurring via glutaredoxins or thioredoxins. Target proteins containing reduction-oxidation (redox) sensitive thiol groups include i) signal transduction pathway proteins, such as phosphatases and mitogen-activated protein kinases, ii) embryogenesis regulating proteins iii) many transcription factors, iv) RNA-binding proteins that direct DNA methylation, and v) proteins involved in histone acetylation, deacetylation or methylation.

Similarly, the tyrosine-specific Protein Tyrosine Phosphatases are intracellular activities lacking disulfide bonds, but they might sense intracellular redox potential through the conserved cysteine in their active sites An intracellular oscillation of oxidant levels has been previously experimentally linked to maintenance of the rate of cell proliferation.

As an example, when chelating redox-active iron present in the endosomal/lysosomal compartment of cultured epithelial cell line HeLa with the iron chelator desferrioxamine, cell proliferation is inhibited.

Thioredoxin (Trx) signaling Is also important in Cancer, as are other aspects of redox signaling. .