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 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 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.

The "Adrenochrome Hypothesis" of Abram Hoffer and Humphry Osmond for the causation of schizophrenia involves the radical oxidation of the neurotransmitter epinephrine to the psychoactive compound adrenochrome.

Progress in biochemistry has enabled us to improve our understanding of redox signaling in general: usually extracellular environment is more oxidized than intracellular. 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. This is important to extracellular proteins, as they are constantly exposed to a variety of proteases, capable of degrading especially easy the proteins with loose conformation. Inside the cell, on the contrary, mildly reducing conditions usually predominate. Cysteine residues are not involved in the formation of disulfide bonds, unless intracellular redox balance is tilted toward oxidant stress. 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. 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. As a consequence, a cell may change its rate of proliferation, or die, depending on the signal networks that it operates.An intracellular oscillation of oxidant levels has been previously experimentally linked to maintenance of the rate of cell proliferation. [Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ. (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. Vol. 275 Issue 5306:1649-52. ] 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 [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. Vol. 35, Issue 7:719-28. ] .

External links

* [http://www.redoxsignaling.com redoxsignaling.com]
* [http://www.doctorproctor.com/crcpap2.htm Review--Free Radicals and Human Disease]

References

1. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ. (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. Vol. 275 Issue 5306:1649-52.

2. 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. Vol. 35, Issue 7:719-28.