Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration
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ORIGINAL ARTICLE
Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration Niyathi Hegde Shah & Elias Aizenman
Received: 9 August 2013 / Revised: 14 September 2013 / Accepted: 14 October 2013 / Published online: 19 November 2013 # Springer Science+Business Media New York 2013
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.
Invited review for Special Issue: “Ion transporters and glutamate receptorindependent mechanisms for ischemic and/or traumatic brain injury.” Guest editors: Dandan Sun & Kristopher Kahle, Translational Stroke Research. N. H. Shah (*) : E. Aizenman (*) Department of Neurobiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, E1456 BST, Pittsburgh, PA 15261, USA e-mail: [email protected] e-mail: [email protected]
Keywords Voltage-gated potassium channels . Kv2.1 . Apoptosis . Ischemia . Ischemic preconditioning . Neuronal hyperexcitability . Epilepsy
Introduction Voltage-gated potassium (Kv) channels are the largest gene family of potassium (K+) channels and are key regulators of neuronal excitability [1–4]. In humans, they are encoded by 40 different genes and categorized into 12 subfamilies, Kv1 through Kv12 [5]. Mammalian Kv channels are tetramers, composed of four α-subunits that surround an ion conduction pore. Each α-subunit contains six α-helical transmembrane domains (S1–S6), a membrane-reentering P loop between S5 and S6, and cytosolic N- and C-termini. Four S5-P-S6 segments line the ion conduction pore, while the S1–S4 sequences are critical for channel voltage sensing and gating. Kv channels mediate outward K+ currents that contribute to membrane repolarization and hyperpolarization, thus
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