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| '''Redox signaling''' is the process wherein ], ] (ROS), and other electronically-activated species act as messengers in biological systems. | |||
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| ==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 ] is a stable free radical. ] noted that white blue-eyed cats are usually deaf and that this combination might be related to some defect in neuronal development secondary to the absence of melanin pigment. In a similar manner, it has been known for centuries that radical-generating ] such as intraocular ] and ] may produce massive vitreous fibrosis (scarring) as they oxidize. We now know that ] likely play a key role in fibrocyte activation.{{Fact|date=May 2009}} | |||
| The "Adrenochrome Hypothesis" of ] and ] for the causation of ] involves the radical oxidation of the neurotransmitter ] and other ]s to the psychoactive compound ]. | |||
| The first modern statement of the hypothesis appears to be that of Proctor<ref>{{cite journal |author=Proctor P |title=Electron-transfer factors in psychosis and dyskinesia |journal=Physiol. Chem. Phys. |volume=4 |issue=4 |pages=349–60 |year=1972 |pmid=4680784 |url=http://www.nitrone.com/72rev.htm}}</ref>, who at a subsequent congress of free radical investigators in 1979 generalized it 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 . The next reference seems to be Bochner and coworkers<ref>{{cite journal |author=Bochner BR, Lee PC, Wilson SW, Cutler CW, Ames BN |title=AppppA and related adenylylated nucleotides are synthesized as a consequence of oxidation stress |journal=Cell |volume=37 |issue=1 |pages=225–32 |year=1984 |month=May |pmid=6373012 |url=http://linkinghub.elsevier.com/retrieve/pii/0092-8674(84)90318-0}}</ref>. | |||
| Progress in biochemistry has enabled us to improve our understanding of redox signaling in general: usually extracellular environment is more oxidized than intracellular.{{Fact|date=May 2009}} 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.{{Fact|date=May 2009}} 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.{{Fact|date=May 2009}} Cysteine residues are not involved in the formation of disulfide bonds, unless intracellular redox balance is tilted toward oxidant stress.{{Fact|date=May 2009}} 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.{{Fact|date=May 2009}} 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{{Fact|date=May 2009}}. As a consequence, a cell may change its rate of proliferation, or die, depending on the signal networks that it operates.{{Fact|date=May 2009}} | |||
| An intracellular oscillation of oxidant levels has been previously experimentally linked to maintenance of the rate of cell proliferation.<ref>{{cite journal |author=Irani K, Xia Y, Zweier JL, ''et al.'' |title=Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts |journal=Science |volume=275 |issue=5306 |pages=1649–52 |year=1997 |month=March |pmid=9054359 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=9054359}}</ref> | |||
| 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<ref>{{cite journal |author=Doulias PT, Christoforidis S, Brunk UT, Galaris D |title=Endosomal and lysosomal effects of desferrioxamine: protection of ] cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest |journal=Free Radic. Biol. Med. |volume=35 |issue=7 |pages=719–28 |year=2003 |month=October |pmid=14583336 |url=http://linkinghub.elsevier.com/retrieve/pii/S0891584903003964}}. </ref>. | |||
| ==External links== | |||
| * | |||
| *{{cite book |first=Peter H. |last=Proctor |chapter=Free Radicals and Human Disease |title=CRC Handbook of Free Radicals and Antioxidants |year=1989 |volume=1 |pages=209–221 |url=http://www.doctorproctor.com/crcpap2.htm}} | |||
| ==References== | |||
| {{reflist}} | |||
| ] | |||
| ] | |||
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