Redox signaling
Redox signaling is the process wherein free radicals, reactive oxygen species (ROS), and other electronically-activated species act as messengers in biological systems.
History
The concept of electronically-activated species as messengers in both normal metabolism and in pathogenesis goes back to the 19th century. For example, the biological pigment melanin is a stable free radical. Charles Darwin noted that melanin-deficient white blue-eyed cats are usually deaf. Further, their deafness might be related to some defect in neuronal development secondary to the absence of melanin pigment. Likewise, it has been long-known that radical-generating transition-series metals such as intraocular copper and iron may produce massive vitreous fibrosis (scarring) as they oxidize. We now know that reactive oxygen species likely play a key role in fibrocyte activation.[1]
The "Adrenochrome Hypothesis" of Abram Hoffer and Humphry Osmond for the causation of schizophrenia involves the radical oxidation of the neurotransmitter epinephrine and other catecholamines to the psychoactive compound adrenochrome.
The first modern statement of the hypothesis appears to be that of Proctor[1], who at a congress of free radical investigators in 1979 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....". This was formally published in a review in 1984 [2]. The next reference seems to be Bochner and coworkers[2].
Further research has enabled us to improve our understanding of redox signaling, a very complicated process. For example, usually extracellular environment is more oxidized than intracellular.[citation needed] This results in proteins and segments thereof that are exposed to the extracellular environment to form disulfide bridges between cysteine amino acid residues. This way, complementary surfaces have the ability to maintain a covalent bond that stabilizes structure.[citation needed] This is important to extracellular proteins, as they are constantly exposed to a variety of proteases, capable of degrading especially easily proteins with loose conformation. Inside the cell, on the contrary, mildly reducing conditions usually predominate.[citation needed] Cysteine residues are not involved in the formation of disulfide bonds, unless intracellular redox balance is tilted toward oxidant stress.[citation needed] The formation of disulfide bonds is capable of altering both conformation and activity of a number of enzymes, most notably of phosphatases. These enzymes usually restrict the activity of protein kinases (protein phosphorylases). Inactivation of a specific phosphatase by oxidant stress results in prolonged activity for the kinases that it controls in a specific cell type. Prolonged activity of specific kinases, in a cell, means that particular intracellular signal cascades are increasingly activated.[citation needed] Such alterations in the intracellular signal cascades, which proceed through successive phosphorylations of particular kinases that operate on a pathway, culminate in phosphorylation of proteins in many cell compartments, such as mitochondria or nucleus. This modification of specific regulatory proteins can result in a number of changes, ranging from ionic signals to wide alterations in patterns of gene expression[citation needed]. As a consequence, a cell may change its rate of proliferation, or die, depending on the signal networks that it operates.[citation needed] An intracellular oscillation of oxidant levels has been previously experimentally linked to maintenance of the rate of cell proliferation.[3] 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[4].
External links
- redoxsignaling.com
- Proctor, Peter H. (1989). "Free Radicals and Human Disease". CRC Handbook of Free Radicals and Antioxidants. Vol. 1. pp. 209–221.
References
- ^ Proctor P (1972). "Electron-transfer factors in psychosis and dyskinesia". Physiol. Chem. Phys. 4 (4): 349–60. PMID 4680784.
- ^ Bochner BR, Lee PC, Wilson SW, Cutler CW, Ames BN (1984). "AppppA and related adenylylated nucleotides are synthesized as a consequence of oxidation stress". Cell. 37 (1): 225–32. PMID 6373012.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Irani K, Xia Y, Zweier JL; et al. (1997). "Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts". Science. 275 (5306): 1649–52. PMID 9054359.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Doulias PT, Christoforidis S, Brunk UT, Galaris D (2003). "Endosomal and lysosomal effects of desferrioxamine: protection of [[ HeLa ]] cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest". Free Radic. Biol. Med. 35 (7): 719–28. PMID 14583336.
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