Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons

Antonucci-Durgan, Dana; Lim, Seung Taik; Vassanelli, Stefano; Trimmer, James S.

doi:10.1016/s0306-4522(01)00476-6

Cited by 116 publications

(167 citation statements)

References 48 publications

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“…1B). Of note, ryanodine receptors, which as mentioned earlier can be gated by DTDP (37), spatially colocalize with Kv2.1 channel clusters in neurons (40).…”

Section: Injurious Oxidant Exposure Leads To Camkii Activation In Neumentioning

confidence: 55%

Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents

McCord

Aizenman

2013

Proc. Natl. Acad. Sci. U.S.A.

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A simultaneous increase in cytosolic Zn 2+ and Ca 2+ accompanies the initiation of neuronal cell death signaling cascades. However, the molecular convergence points of cellular processes activated by these cations are poorly understood. Here, we show that Ca 2+ -dependent activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is required for a cell death-enabling process previously shown to also depend on Zn 2+ . We have reported that oxidant-induced intraneuronal Zn 2+ liberation triggers a syntaxin-dependent incorporation of Kv2.1 voltage-gated potassium channels into the plasma membrane. This channel insertion can be detected as a marked enhancement of delayed rectifier K + currents in voltage clamp measurements observed at least 3 h following a short exposure to an apoptogenic stimulus. This current increase is the process responsible for the cytoplasmic loss of K + that enables protease and nuclease activation during apoptosis. In the present study, we demonstrate that an oxidative stimulus also promotes intracellular Ca 2+ release and activation of CaMKII, which, in turn, modulates the ability of syntaxin to interact with Kv2.1. Pharmacological or molecular inhibition of CaMKII prevents the K + current enhancement observed following oxidative injury and, importantly, significantly increases neuronal viability. These findings reveal a previously unrecognized cooperative convergence of Ca 2+ -and Zn 2+ -mediated injurious signaling pathways, providing a potentially unique target for therapeutic intervention in neurodegenerative conditions associated with oxidative stress.

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“…1B). Of note, ryanodine receptors, which as mentioned earlier can be gated by DTDP (37), spatially colocalize with Kv2.1 channel clusters in neurons (40).…”

Section: Injurious Oxidant Exposure Leads To Camkii Activation In Neumentioning

confidence: 55%

Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents

McCord

Aizenman

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Rat brain membranes were prepared and treated with purified phosphatases as described previously (Misonou et al, 2004). Proteins were separated on 7.5% SDS-PAGE, transferred to nitrocellulose membrane, and immunoblotted with anti-Kv2.1 mouse monoclonal antibody K89/41 (Antonucci et al, 2001) or anti-Kv4.2 mouse monoclonal antibody K57/1 . The blots were incubated with HRP-conjugated secondary antibodies (MP Biomedicals, Irvine, CA) followed by enhanced chemiluminescence reagent (PerkinElmer, Wellesley, MA).…”

Section: Methodsmentioning

confidence: 99%

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.

174

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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“…The rabbit polyclonal antibodies used as primary antibodies were anti-Kv2.1e, generated against the S1-S2 extracellular region of Kv2.1 (Lim et al, 2000); KC, generated against the cytoplasmic distal C-terminal end of Kv2.1 (Trimmer, 1991); anti-Kv1.4N, generated against the cytoplasmic N-terminal domain of Kv1.4 (Rhodes et al, 1995); and anti-HA (Zymed, San Francisco, CA). The mouse monoclonal antibodies (mAbs) used as primary antibodies were K39/25, generated against the S1-S2 extracellular region of Kv2.1 (Lim et al, 2000); K89/41, generated against the cytoplasmic distal C-terminal end of Kv2.1 (Antonucci et al, 2001); K75/41, generated against the cytoplasmic C-terminal domain of Kv4.3 (Rhodes et al, 2004); K63/39, generated against the cytoplasmic C terminus of Kv1.4 (J. S. Trimmer, unpublished data); and anti-myc (19E10; American Type Culture Collection). The anti-Kv channel mouse mAbs are available from NeuroMab (www.neuromab.org), a not-for profit supplier of monoclonal antibodies administered through the University of California.…”

Section: Methodsmentioning

confidence: 99%

“…Kv2.1 is an abundant delayed rectifier type Kv channel expressed in most central neurons (Murakoshi and Trimmer, 1999;Antonucci et al, 2001;Malin and Nerbonne, 2002), where it is found at high densities in large somatodendritic clusters (Trimmer, 1991;Hwang et al, 1993;Scannevin et al, 1996). Knock-down of Kv2.1 in rat hippocampal neurons, where it contributes the majority of I K currents (Murakoshi and Trimmer, 1999), leads to enhanced excitability, especially during highfrequency synaptic transmission, suggesting a critical role for Kv2.1 in regulating membrane excitability (Du et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Interdomain Cytoplasmic Interactions Govern the Intracellular Trafficking, Gating, and Modulation of the Kv2.1 Channel

Mohapatra¹,

Siino²,

Trimmer³

2008

J. Neurosci.

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Voltage-gated potassium (Kv) channels comprise four transmembrane ␣ subunits, often associated with cytoplasmic ␤ subunits that impact channel expression and function. Here, we show that cell surface expression, voltage-dependent activation gating, and phosphorylation-dependent modulation of Kv2.1 are regulated by cytoplasmic N/C interaction within the ␣ subunit. Kv2.1 surface expression is greatly reduced by C-terminal truncation. Tailless Kv2.1 channels exhibit altered voltage-dependent gating properties and lack the bulk of the phosphorylation-dependent modulation of channel gating. Remarkably, the soluble C terminus of Kv2.1 associates with tailless channels and rescues their expression, function, and phosphorylation-dependent modulation. Soluble N and C termini of Kv2.1 can also interact directly. We also show that the N/C-terminal interaction in Kv2.1 is governed by a 34 aa motif in the juxtamembrane cytoplasmic C terminus, and a 17 aa motif located in the N terminus at a position equivalent to the ␤ subunit binding site in other Kv channels. Deletion of either motif disrupts N/C-terminal interaction and surface expression, function, and phosphorylationdependent modulation of Kv2.1 channels. These findings provide novel insights into intrinsic mechanisms for the regulation of Kv2.1 trafficking, gating, and phosphorylation-dependent modulation through cytoplasmic N/C-terminal interaction, which resembles ␣/␤ subunit interaction in other Kv channels.

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Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons

Cited by 116 publications

References 48 publications

Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents

Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents

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

Interdomain Cytoplasmic Interactions Govern the Intracellular Trafficking, Gating, and Modulation of the Kv2.1 Channel

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Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons

Cited by 116 publications

References 48 publications

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

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

Interdomain Cytoplasmic Interactions Govern the Intracellular Trafficking, Gating, and Modulation of the Kv2.1 Channel

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Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents

Convergent Ca ²⁺ and Zn ²⁺ signaling regulates apoptotic Kv2.1 K ⁺ currents