A constitutively open potassium channel formed by KCNQ1 and KCNE3

Schroeder, Björn C.; Waldegger, Siegfried; Fehr, Susanne; Bleich, Markus; Warth, Richard; Greger, R.; Jentsch, Thomas J.

doi:10.1038/35003200

Cited by 464 publications

(575 citation statements)

References 30 publications

(32 reference statements)

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“…8,26 In contrast, co-assembly of KCNQ1 with KCNE3 produces a current with nearly instantaneous activation. 27 In colonic crypts, these KCNQ1:KCNE3 channels mediate basolateral K + recycling required for Cl − secretion and their expression is regulated by estrogens. 28 In the stomach, KCNQ1:KCNE2 regulates acid secretion.…”

Section: Discussionmentioning

confidence: 99%

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

et al. 2015

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Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, Po0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, Po0.001) and LQT3 (57%, P = 0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, Po0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.

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Section: Discussionmentioning

confidence: 99%

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

et al. 2015

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“…Although functional channels are obtained by expression of K v 7 ␣-subunits alone, ␤-subunits belonging to the KCNE family are reported to influence the expression, pharmacology, and voltage-dependence of the ␣-subunits (Schroeder et al, 2000b;Wang et al, 2000;Grunnet et al, 2002). There are five known ␣-subunits (K v 7.1-K v 7.5), and the sequence alignment of the hydrophobic regions divides them into two groups, one comprising K v 7.1 and the other K v 7.2 to K v 7.5.…”

mentioning

confidence: 99%

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels

Korsgaard

Hartz²,

Brown³

et al. 2005

J Pharmacol Exp Ther

126

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Neuronal K v 7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K v 7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K v 7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K v 7 channels, whereas its Renantiomer was a negative modulator. By contrast, at the K v 7.1 and the large conductance Ca 2ϩ -activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA A receptors (␣ 1 ␤ 2 ␥ 2s and ␣ 2 ␤ 2 ␥ 2s ) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S-and R-forms exhibited opposing effects on neuronal K v 7 channel subtypes allowed us to assess the potential role of K v 7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K v 7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.

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“…4C). These results show that secramine B selectively attenuated K + efflux through a cAMPregulated and Ba 2+ -sensitive basolateral K + efflux pathway, presumably via the K + channel KCNQ1/KCNE3 [2].…”

Section: Secramine Inhibits the Basolateral Camp-gated K + Effluxmentioning

confidence: 63%

“…Secramine B acted by inhibiting a basolateral cAMP-dependent K + channel, likely comprised of the voltage-gated KCNQ1 and its modulatory KCNE3 subunits [2]. This channel, but not the related KCNE1, is expressed in the T84 cells and opens in response to cAMP agonists [2].…”

Section: Discussionmentioning

confidence: 99%

“…Export of K + across the basolateral membrane maintains the electrochemical potential required to sustain apical Cl -secretion. In the intestine, this is likely accomplished by the KCNQ1/KCNE3 and the KCNN4 channels, gated open by intracellular cAMP or Ca 2+ , respectively [2,3]. Although the general features of cAMP and Ca 2+ -induced chloride secretion are understood, such as the channels required to sustain chloride secretion, little is known about the coordinated activation and regulation of these chloride secretion pathways.…”

Section: Introductionmentioning

confidence: 99%

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The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

Pelish

Ciesla

Tanaka

et al. 2006

Biochemical Pharmacology

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Cyclic AMP-(cAMP) and calcium-dependent agonists stimulate chloride secretion through the coordinated activation of distinct apical and basolateral membrane channels and ion transporters in mucosal epithelial cells. Defects in the regulation of Cl -transport across mucosal surfaces occur with cystic fibrosis and V. cholerae infection and can be life threatening. Here we report that secramine B, a small molecule that inhibits activation of the Rho GTPase Cdc42, reduced cAMPstimulated chloride secretion in the human intestinal cell line T84. Secramine B interfered with a cAMP-gated and Ba 2+ -sensitive K + channel, presumably KCNQ1/KCNE3. This channel is required to maintain the membrane potential that sustains chloride secretion. In contrast, secramine B did not affect the Ca 2+ -mediated chloride secretion pathway, which requires a separate K + channel activity from that of cAMP. Pirl1, another small molecule structurally unrelated to secramine B that also inhibits Cdc42 activation in vitro, similarly inhibited cAMPdependent but not Ca 2+ -dependent chloride secretion. These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K + conductance in intestinal epithelial cells.

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A constitutively open potassium channel formed by KCNQ1 and KCNE3

Cited by 464 publications

References 30 publications

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels

The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

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A constitutively open potassium channel formed by KCNQ1 and KCNE3

Cited by 464 publications

References 30 publications

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal Kv7 Channels

The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

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Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels