Calcium- and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia.
Ischemic stroke is often accompanied by neuronal hyperexcitability (i.e., seizures), which aggravates brain damage. Therefore, suppressing stroke-induced hyperexcitability and associated excitoxicity is a major focus of treatment for ischemic insults. Both ATP-dependent and Ca2+-activated K+ channels have been implicated in protective mechanisms to suppress ischemia-induced hyperexcitability. Here we provide evidence that the localization and function of Kv2.1, the major somatodendritic delayed rectifier voltage-dependent K+ channel in central neurons, is regulated by hypoxia/ischemia-induced changes in metabolic state and intracellular Ca2+ levels. Hypoxia/ischemia in rat brain induced a dramatic dephosphorylation of Kv2.1 and the translocation of surface Kv2.1 from clusters to a uniform localization. In cultured rat hippocampal neurons, chemical ischemia (CI) elicited a similar dephosphorylation and translocation of Kv2.1. These events were reversible and were mediated by Ca2+ release from intracellular stores and calcineurin-mediated Kv2.1 dephosphorylation. CI also induced a hyperpolarizing shift in the voltage-dependent activation of neuronal delayed rectifier currents (IK), leading to enhanced IK and suppressed neuronal excitability. The IK blocker tetraethylammonium reversed the ischemia-induced suppression of excitability and aggravated ischemic neuronal damage. Our results show that Kv2.1 can act as a novel Ca2+- and metabolic state-sensitive K+ channel and suggest that dynamic modulation of IK/Kv2.1 in response to hypoxia/ischemia suppresses neuronal excitability and could confer neuroprotection in response to brief ischemic insults.
Misonou
Hiroaki
H
Department of Pharmacology, School of Medicine, University of California, Davis, California 95616, USA. hmisono@ucdavis.edu
Mohapatra
Durga P
DP
Menegola
Milena
M
Trimmer
James S
JS
D000758:Anesthesia; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002245:Carbon Dioxide; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D009994:Osmolar Concentration; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000209:etiology* / Q000378:metabolism*; D051669:Shab Potassium Channels / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology; D014018:Tissue Distribution
D051668:Delayed Rectifier Potassium Channels; D018696:Neuroprotective Agents; D010455:Peptides; D026902:Potassium Channel Blockers; D051669:Shab Potassium Channels; D002245:Carbon Dioxide; D019789:Tetraethylammonium; C064719:iberiotoxin; D019703:Calcineurin; D002118:Calcium