Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

Abstract

Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system, and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated increased K+ efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in neurodegenerative disorders such as Alzheimer’s disease and stroke. In contrast, some forms of neuronal activity can dramatically alter Kv2.1 channel phosphorylation levels and influence their localization. These changes are normally accompanied by modifications in channel voltage-dependence, which may be neuroprotective within the context of ischemic injury. Kv1 and Kv7 channel dysfunction leads to neuronal hyperexcitability that critically contributes to the pathophysiology of human clinical disorders such as episodic ataxia and epilepsy. This review summarizes the neurotoxic, neuroprotective, and neuroregulatory roles of Kv channels, and highlights the consequences of Kv channel dysfunction on neuronal physiology. The studies described in this review thus underscore the importance of normal Kv channel function in neurons, and emphasize the therapeutic potential of targeting Kv channels in the treatment of a wide range of neurological diseases.

Kv7 channels regulate pairwise spiking covariability in health and disease

“…These channels are present throughout the nervous system (Brown and Passmore 2009;Delmas and Brown 2005;Jentsch 2000), and their dysfunction is involved in several disease states (Cooper and Jan 2003;Li et al 2013;Passmore et al 2003;Shah and Aizenman 2014;Zheng et al 2012). Using a well-established theoretical framework to study correlation transfer in spiking neurons (de la Rocha et al 2007), we showed that the recruitment of Kv7 conductances provides an input-driven negative feedback that cancels correlating inputs and reduces the covariability of pairwise spiking activity in model neurons.…”

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

“…Zinc also contributes to neuronal death in hypoxic-ischemic injury (34,35,(47)(48)(49) by interfering with mitochondrial and metabolic functions (50,51), altering ion fluxes (52), and other mechanisms (53). Abnormalities in zinc homeostasis may be important in chronic neurodegenerative diseases, such as Alzheimer's (54) and amyotrophic lateral sclerosis (55)(56)(57), and have been shown to play a key role in oxidative stress-induced death in neurons and oligodendrocytes (58,59).…”

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

“…Finally, increased K þ conductance and the gradual accumulation of extracellular K þ that occur during ischemia generally contribute to membrane hyperpolarization and repolarization thereby depressing neuronal excitability. 25 This ionic imbalance may effectively inhibit SD elicitation as well.…”