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PMID: 16319318 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Calcium- and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 48 ·2005-11-30 ·Pages 11184-93

Misonou H, Mohapatra DP, Menegola M, Trimmer JS

Abstract

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.

MeSH Terms
Anesthesia Animals Biological Transport Brain/metabolism Brain Ischemia/complications Calcineurin/metabolism Calcium/metabolism Carbon Dioxide Cells, Cultured Delayed Rectifier Potassium Channels/drug effects Electrophysiology Hippocampus/metabolism Intracellular Membranes/metabolism Neurons/metabolism Neuroprotective Agents/metabolism Osmolar Concentration Peptides/pharmacology Phosphorylation Potassium Channel Blockers/pharmacology Rats Seizures/etiology,metabolism Shab Potassium Channels/metabolism Subcellular Fractions/metabolism Tetraethylammonium/pharmacology Tissue Distribution
Chemicals
Delayed Rectifier Potassium Channels Neuroprotective Agents Peptides Potassium Channel Blockers Shab Potassium Channels Carbon Dioxide Tetraethylammonium iberiotoxin Calcineurin Calcium
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Misonou Hiroaki
Department of Pharmacology, School of Medicine, University of California, Davis, California 95616, USA. hmisono@ucdavis.edu
Mohapatra Durga P
Menegola Milena
Trimmer James S
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.3370-05.2005
Email
hmisono@ucdavis.edu
Published
2005-11-30
Pages
11184-93
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6725654
Subset
IM
Grants
NCRR NIH HHS · C06 RR012088 · United States
NCRR NIH HHS · C06 RR-12088-01 · United States
NINDS NIH HHS · NS42225 · United States
NCI NIH HHS · P01 CA095616 · United States
NINDS NIH HHS · R01 NS042225 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.3370-05.2005 PMC Full Text View journal details
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