Oxidation of K+ Channels in Aging and Neurodegeneration

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.

Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging

“…In addition to the age-related modification of Kv and BK channel function mentioned above (Sesti, 2016), P/Q type Cav channels implicated in SD evolution were shown to be affected by aging, as well. Protein levels of P/Q type Cav channels in synaptosomes extracted from the cerebral cortex significantly decreased at preserved synaptic density Fig.…”

“…It is conceivable that the stimulus applied is dissipated in the tissue before SD is ignited. Some evidence suggest that the excitability of the aged nervous tissue is lower, because the age-specific increase in the production of reactive oxygen species modifies the operation of the redox-sensitive K + channels (Sesti, 2016) (Fig. 2B).…”

“…2B). This process may modulate the oligomer formation, permeation and gating properties of Kv channels and BK channels (Sesti, 2016), but it remains to be explored whether these changes manifest at the level of SD evolution. Age may also hamper the recruitment of the minimum tissue volume required for SD initiation.…”

“…B, Agerelated dysfunction of the Na + /K + ATPase may contribute to K + accumulation in the interstitial space to trigger SD. While little is certain about the impact of aging on voltage-gated Na + channels (Nav), the augmented production of reactive oxygen species with aging may alter voltage-gated K + channel (Kv) function to reduce the excitability of the nervous tissue (Sesti et al, 2016). Finally, aging may suppress the expression of P/Q type voltagegated Ca 2+ channels (Cav) (Iwamoto et al, 2004) that may increase SD threshold.…”

Emerging Anti-Aging Strategies - Scientific Basis and Efficacy

“…Oxidative stress has a significant influence in the development of many age-related diseases, which include arthritis, diabetes, dementia, stroke, cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, and metabolic syndromes [159][160][161][162][163][164]. Reactive oxygen species (ROS) are generated within the biological system to regulate cellular activities such as cell survival, stressor responses, ion channels, and inflammation [165,166]. However, the elevation of ROS is linked to the onset and progression of aging.…”