Abstract
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels—which are key to neuronal excitability—in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. From this arose the idea that oxidation of ion channels by ROS is one of the culprits for neuronal aging. Aging-dependent oxidative modification of voltage-gated potassium (K+) channels was initially demonstrated in the nematode Caenorhabditis elegans and more recently in the mammalian brain. Specifically, oxidation of the delayed rectifier KCNB1 (Kv2.1) and of Ca2+- and voltage sensitive K+ channels have been established suggesting that their redox sensitivity contributes to altered excitability, progression of healthy aging and of neurodegenerative disease. Here I discuss the implications that oxidation of K+ channels by ROS may have for normal aging, as well as for neurodegenerative disease.
Highlights
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity
Wild type KVS-1 currents exhibit rapid activation-inactivation and as such can be described as A-type; their inactivation kinetics are slower than typical A-type kinetics due to the presence of the N-inactivation regulatory domain (NIRD) which hinders the inactivation ball [31]
The simple redox-dependence of KVS-1, along with the fact that C. elegans is genetically tractable and that the behavior mediated by the neurons where KVS-1 operates can be experimentally assessed, allowed us to study the effects of oxidation of the channel by ROS in aging worms [32]
Summary
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. The redox environment of the cell becomes altered in favor of oxidation by an increased production of ROS and/or a decrease in antioxidant defenses. K+ channels and aging breakthrough came recently, when we showed that in C. elegans, K+ channels undergo age-dependent oxidation but as a result of this, they impair neuronal function.
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