Potassium-dependent Changes in the Conformation of the Kv2.1 Potassium Channel Pore

Immke, David; Wood, Michael J.; Kiss, László; Korn, Stephen J.

doi:10.1085/jgp.113.6.819

Cited by 81 publications

(169 citation statements)

References 32 publications

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“…As a positive control, 20 mM TEA at 0 mV was shown to produce ϳ85% block at time 0 and ϳ88% block after 5 min. This essentially instantaneous intracellular block by TEA was reported previously using the same TEA concentration and technique (Immke et al, 1999). These data suggest that the high-affinity site of TA279 is accessed from outside the cell and does not require TA279 to cross the plasma membrane.…”

Section: Resultssupporting

confidence: 84%

1,4-Diazabicyclo[2.2.2]octane Derivatives: A Novel Class of Voltage-Gated Potassium Channel Blockers

Gordon

Cohen²,

Engel³

et al. 2005

Mol Pharmacol

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Voltage-gated potassium (Kv) channels are targets for therapeutic drugs in the treatment of pathologic conditions including cardiac arrhythmia and epilepsy. In this study, we synthesized three classes of novel polyammonium compounds incorporating the bicyclic unit 1,4-diazabicyclo[2.2.2]octane (DABCO) and tested their action on three representative mammalian Kv channels (Kv2.1, Kv3.4, and Kv4.2) expressed in Xenopus laevis oocytes. Nonsubstituted DABCO did not block the Kv channels tested. Simple DABCO monostrings and diDABCO strings inhibited Kv2.1 and Kv3.4 channels, with potency increasing with string length for both these DABCO classes. Both Kv2.1 and Kv3.4 were most sensitive to C 16 monostrings, with IC 50 values of 1.9 and 0.6 M, respectively. For compounds comprising two DABCO groups separated by an aromatic ring, inhibition depended upon relative positioning of the two DABCO groups, and only the para form (JC638.2␣) was active, blocking Kv2.1 with an IC 50 of 186 M. Kv4.2 channels were relatively insensitive to all compounds tested. Unlike the tetraethylammonium ion (TEA), neither JC638.2␣ nor C 16 monostring TA279 produced block when applied intracellularly via the recording electrode to Kv2.1 channels expressed in Chinese hamster ovary cells, suggesting against an internal site of action. However, JC638.2␣ protected an introduced cysteine (K356C) in the Kv2.1 outer pore from permanent modification by methanethiosulfonate ethyltrimethylammonium (MTSET). These data suggest that JC638.2␣ occupies an external binding site similar to that of TEA in the Kv2.1 outer pore, but with much higher affinity than TEA. These DABCO salts represent a new class of Kv channel blockers, some with higher potencies than any previously described quaternary ammonium ions. The potential for synthesis of an array of modular derivatives suggests that DABCO compounds hold promise as probes of Kv channel structure and identity and as potential therapeutic agents.

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Section: Resultssupporting

confidence: 84%

1,4-Diazabicyclo[2.2.2]octane Derivatives: A Novel Class of Voltage-Gated Potassium Channel Blockers

Gordon

Cohen²,

Engel³

et al. 2005

Mol Pharmacol

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“…Previous studies have shown that the bulk (Ն80%) of I K in hippocampal and cortical pyramidal neurons is contributed by Kv2.1 (Murakoshi and Trimmer, 1999;Du et al, 2000;Pal et al, 2003). We found that the broadspectrum K ϩ channel blocker TEA when used at 5 mM [the K i for TEA block of Kv2.1 is 1-5 mM based on studies of recombinant rat brain Kv2.1 in heterologous cells (Shi et al, 1994;Immke et al, 1999)] effectively blocked (90.0 Ϯ 0.2% inhibition) I K in control neurons. These data suggest that TEA effectively blocks the major Kv2.1 component of I K .…”

Section: Chemical Ischemia Alters the Voltage-dependent Activation Ofmentioning

confidence: 79%

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.

173

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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“…Interestingly, the inactivation of TWIK-2 was impaired in K ϩ -rich conditions. The inactivation of Shaker-type K ϩ channels is similarly highly temperature-dependent and sensitive to cations (30,31). The rate of the conformational change that underlies Shaker C-type inactivation is determined largely by the exit rate of K ϩ from the pore, and occupancy of the selectivity filter by K ϩ slows the rate of inactivation (31).…”

Section: Discussionmentioning

confidence: 99%

“…The inactivation of Shaker-type K ϩ channels is similarly highly temperature-dependent and sensitive to cations (30,31). The rate of the conformational change that underlies Shaker C-type inactivation is determined largely by the exit rate of K ϩ from the pore, and occupancy of the selectivity filter by K ϩ slows the rate of inactivation (31). Inactivation of Shaker K ϩ channels involves the amino-terminal domain (fast N type inactivation) as well as the carboxyl-terminal region (slow C type inactivation).…”

Section: Discussionmentioning

confidence: 99%

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TWIK-2, an Inactivating 2P Domain K+ Channel

Patel

Maingret

Magnone

et al. 2000

Journal of Biological Chemistry

104

111

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We cloned human and rat TWIK-2 and expressed this novel 2P domain K ؉ channel in transiently transfected COS cells. TWIK-2 is highly expressed in the gastrointestinal tract, the vasculature, and the immune system. Rat TWIK-2 currents are about 15 times larger than human TWIK-2 currents, but both exhibit outward rectification in a physiological K ؉ gradient and mild inward rectification in symmetrical K ؉ conditions. TWIK-2 currents are inactivating at depolarized potentials, and the kinetic of inactivation is highly temperature-sensitive. TWIK-2 shows an extremely low conductance, which prevents the visualization of discrete single channel events. The inactivation and rectification are intrinsic properties of TWIK-2 channels. In a physiological K ؉ gradient, TWIK-2 is half inhibited by 0.1 mM Ba 2؉ , quinine, and quinidine. Finally, cysteine 53 in the M1P1 external loop is required for functional expression of TWIK-2 but is not critical for subunit self-assembly. TWIK-2 is the first reported 2P domain K ؉ channel that inactivates. The base-line, transient, and delayed activities of TWIK-2 suggest that this novel 2P domain K ؉ channel may play an important functional role in cell electrogenesis.

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Potassium-dependent Changes in the Conformation of the Kv2.1 Potassium Channel Pore

Cited by 81 publications

References 32 publications

1,4-Diazabicyclo[2.2.2]octane Derivatives: A Novel Class of Voltage-Gated Potassium Channel Blockers

1,4-Diazabicyclo[2.2.2]octane Derivatives: A Novel Class of Voltage-Gated Potassium Channel Blockers

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

TWIK-2, an Inactivating 2P Domain K+ Channel

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