Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells

Wickenden, Alan D.; Zou, Anruo; Wagoner, P. Kay; Jegla, Timothy

doi:10.1038/sj.bjp.0703861

Cited by 92 publications

(80 citation statements)

References 16 publications

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“…Both linopirdine and XE991 evoked depolarization (Fig. 3, A and B), which could take several minutes to reach steady state and often showed only partial recovery over the time course of the experiments (Յ30 min), as found previously with recombinant KCNQ channels (Wickenden et al, 2001). Linopirdine depolarized cells by 9 mV (from Ϫ45 Ϯ 3 to Ϫ36 Ϯ 3 mV; n ϭ 8, p Ͻ 0.05) at 1 M and by 15 mV (from Ϫ48 Ϯ 3 to Ϫ33 Ϯ 7 mV; n ϭ 5, p Ͻ 0.05) at 10 M. Similar responses were seen with XE991 (Fig.…”

Section: Electrophysiological Effects Of Kcnq Channelmentioning

confidence: 71%

KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle

Joshi¹,

Sedivy²,

Hodyc³

et al. 2009

J Pharmacol Exp Ther

106

124

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Potassium channels are central to the regulation of pulmonary vascular tone. The smooth muscle cells of pulmonary artery display a background K ϩ conductance with biophysical properties resembling those of KCNQ (K V 7) potassium channels. Therefore, we investigated the expression and functional role of KCNQ channels in pulmonary artery. The effects of selective KCNQ channel modulators were investigated on K ϩ current and membrane potential in isolated pulmonary artery smooth muscle cells (PASMCs), on the tension developed by intact pulmonary arteries, and on pulmonary arterial pressure in isolated perfused lungs and in vivo. The KCNQ channel blockers, linopirdine and XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone], inhibited the noninactivating background K ϩ conductance in PASMCs and caused depolarization, vasoconstriction, and raised pulmonary arterial pressure without constricting several systemic arteries or raising systemic pressure. The KCNQ channel openers, retigabine and flupirtine, had the opposite effects. PASMCs were found to express KCNQ4 mRNA, at higher levels than mesenteric artery, along with smaller amounts of KCNQ1 and 5. It is concluded that KCNQ channels, most probably KCNQ4, make an important contribution to the regulation of pulmonary vascular tone, with a greater contribution in pulmonary compared with systemic vessels. The pulmonary vasoconstrictor effect of KCNQ blockers is a potentially serious side effect, but the pulmonary vasodilator effect of the openers may be useful in the treatment of pulmonary hypertension.

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Section: Electrophysiological Effects Of Kcnq Channelmentioning

confidence: 71%

KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle

Joshi¹,

Sedivy²,

Hodyc³

et al. 2009

J Pharmacol Exp Ther

106

124

View full text Add to dashboard Cite

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“…Several classes of small-molecule activators for KCNQ channels have been identified and they differ in chemical structure, mode of action, and target selectivity (29)(30)(31)(32)(33)(34). For example, among five KCNQ channels, KCNQ1 to KCNQ5 (or Kv7.1-Kv7.5), Retigabine has a rank order of potency as KCNQ3 > KCNQ2 > KCNQ4 = KCNQ5 >> KCNQ1 according to the available data (34), whereas ZnPy has a rank order of efficacy as KCNQ4 >> KCNQ2 > KCNQ1 >> KCNQ3 (32).…”

Section: Discussionmentioning

confidence: 99%

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Lin

Mattmann

et al. 2013

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

122

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Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1-KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1-KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or I Ks , is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether I Ks is mediated by KCNE-saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments I Ks current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n channels are present as components of I Ks and are pharmacologically distinct from KCNE-saturated KCNQ1-KCNE1 channels.cardiac physiology | drug | long QT | pharmacology

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“…The drug is therefore a "potassium channel opener." Subsequently, it was found that retigabine is specific for M-type potassium current, which is carried by KCNQ (Kv7)-type potassium channels (Rundfeldt and Netzer, 2000b;Main et al, 2000;Wickenden et al, 2001). M-current is a slowly activating current whose threshold is near resting potential.…”

Section: Retigabinementioning

confidence: 99%

“…There are four known neuronal KCNQ subunits (KCNQ2-5 or Kv7.2-7.5), which are homologous to KCNQ1 (KvLQT or Kv7.1), a cardiac potassium channel involved in one form of the long QT syndrome (Jentsch, 2000). Retigabine acts on all neuronal KCNQ subunits, but not on KCNQ1 which is expressed in cardiac muscle (Tatulian et al, 2001;Wickenden et al, 2001). Through the use of chimeras it has been possible to define elements of the KCNQ structure that are critical to the effects of retigabine on gating and presumably to its binding (Wuttke et al, 2005;Schenzer et al, 2005).…”

Section: Retigabinementioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

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Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells

Cited by 92 publications

References 16 publications

KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle

KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Diverse mechanisms of antiepileptic drugs in the development pipeline

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