Kv2.1: A Voltage-Gated K+ Channel Critical to Dynamic Control of Neuronal Excitability

Misonou, Hiroaki; Mohapatra, Durga P.; Trimmer, James S.

doi:10.1016/j.neuro.2005.02.003

Cited by 184 publications

(166 citation statements)

References 61 publications

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“…We hypothesize that disruption of neuronal membrane integrity by insertion of (proto-)fibrillar A␤ before plaque formation yields robust changes to V R . Subsequent disruption of, for instance, voltagedependent channel functions (Talley et al, 2003;Ye et al, 2003;Misonou et al, 2005;Plant et al, 2006;Lima et al, 2008) pertinent to maintain a stable, hyperpolarized plasmalemmal membrane potential may underscore sustained membrane depolarization. This notion is also consistent with the observations of lowered seizure thresholds after systemic challenge with pentylentetrazol not only in plaque-bearing APP transgenic mice (Palop et al, 2007) but also in those with elevated levels of soluble A␤ aggregates but no plaques (Del Vecchio et al, 2004;Palop et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

558

544

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Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid ␤ (A␤) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of A␤1-42 or A␤25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied A␤ (proto-)fibrils. Overall, these data identify fibrillar A␤ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

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Section: Discussionmentioning

confidence: 99%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

558

544

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“…We found previously that increased neuronal activity induced by seizures or glutamate stimulation changes Kv2.1 phosphorylation state and localization and yields increased amplitude of hippocampal neuron I K /Kv2.1 attributable to hyperpolarizing shifts in voltage-dependent activation (Misonou et al, 2004). Such enhanced activity of Kv2.1 under conditions of hyperexcitability is predicted to provide homeostatic suppression of neuronal activity (Surmeier and Foehring, 2004;Misonou et al, 2005).…”

Section: Introductionmentioning

confidence: 95%

Calcium- and Metabolic State-Dependent Modulation of the Voltage-Dependent Kv2.1 Channel Regulates Neuronal Excitability in Response to Ischemia

Misonou¹,

Mohapatra²,

Menegola³

et al. 2005

J. Neurosci.

169

275

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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 Ca 2ϩ -activated K ϩ 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 ϩ channel in central neurons, is regulated by hypoxia/ischemia-induced changes in metabolic state and intracellular Ca 2ϩ 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 Ca 2ϩ 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 (I K ), leading to enhanced I K and suppressed neuronal excitability. The I K 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 Ca 2ϩ -and metabolic state-sensitive K ϩ channel and suggest that dynamic modulation of I K /Kv2.1 in response to hypoxia/ischemia suppresses neuronal excitability and could confer neuroprotection in response to brief ischemic insults.

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“…K v β1.1-deficient mice also exhibit reductions in both frequency-dependent spike broadening and the slow after hyperpolarization, modulation of which has been proposed as a learning and memory mechanism (Giese et al 1998(Giese et al , 2001Murphy et al 2004). Meanwhile, clusters of K v 2.1 channels account for the somatodendritic I K (Murakoshi and Trimmer 1999;Du et al 2000;Pal et al 2003) and are necessary for regulating both intrinsic and neuronal excitability during high-frequency stimulation (Du et al 2000;Misonou et al 2005). Excitotoxic Ca 2+ -dependent dephosphorylation of K v 2.1 channels causes cluster dispersion (Misonou et al 2004;Misonou et al 2005), shifts the K v 2.1 activation curve to more hyperpolarized potentials, and increases the open channel probability (Murakoshi et al 1997).…”

Section: K V Channels and Learning And Memorymentioning

confidence: 99%

“…Meanwhile, clusters of K v 2.1 channels account for the somatodendritic I K (Murakoshi and Trimmer 1999;Du et al 2000;Pal et al 2003) and are necessary for regulating both intrinsic and neuronal excitability during high-frequency stimulation (Du et al 2000;Misonou et al 2005). Excitotoxic Ca 2+ -dependent dephosphorylation of K v 2.1 channels causes cluster dispersion (Misonou et al 2004;Misonou et al 2005), shifts the K v 2.1 activation curve to more hyperpolarized potentials, and increases the open channel probability (Murakoshi et al 1997). K v 2.1 dephosphorylation also results in a dendritic beading correlated with diminished LTP (Misonou et al 2004).…”

Section: K V Channels and Learning And Memorymentioning

confidence: 99%

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Keblesh

Xiong

2008

J Neuroimmune Pharmacol

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Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD), a severe form of HIV-associated neurocognitive disorders (HAND), describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (brain perivascular macrophages and microglia) releasing immune and viral products in the brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates voltage-gated potassium (K v ) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find that HAD-related alterations in cellular and viral products can increase neuronal K v channel activity, leading to neuronal dysfunction and cognitive deficits. Thus, neuronal K v channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.

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Kv2.1: A Voltage-Gated K+ Channel Critical to Dynamic Control of Neuronal Excitability

Cited by 184 publications

References 61 publications

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Calcium- and Metabolic State-Dependent Modulation of the Voltage-Dependent Kv2.1 Channel Regulates Neuronal Excitability in Response to Ischemia

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

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