KCNE4 is an inhibitory subunit to the KCNQ1 channel

Grunnet, Morten; Jespersen, Thomas; Rasmussen, Hanne B.; Ljungstrøm, Trine; Jørgensen, Nanna K.; Olesen, Søren‐Peter; Klærke, Dan A.

doi:10.1113/jphysiol.2002.017301

Cited by 142 publications

(152 citation statements)

References 36 publications

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“…Although these results cannot rule out Q1-E1 complex assembly in the cis-Golgi, the sheer abundance of unpartnered E1 peptides in the ER and co-immunoprecipitation of the immature and unglycosylated E1 with Q1 strongly suggest that Q1-E1 complex assembly occurs in the ER. An ER-based assembly for Q1-E1 complexes directly contradicts two previous functional studies where it was proposed that complex assembly occurs at the plasma membrane (14,15). The basis for this proposal was that Xenopus oocytes expressing unpartnered Q1 K ϩ currents could be converted to KCNE-modulated currents within 24 h by a subsequent injection of KCNE mRNA.…”

Section: Discussionmentioning

confidence: 53%

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KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

Chandrasekhar

Bas

Kobertz

2006

Journal of Biological Chemistry

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KCNE peptides are a class of type I transmembrane ␤ subunits that assemble with and modulate the gating and ion conducting properties of a variety of voltage-gated K ؉ channels. Accordingly, mutations that disrupt the assembly and trafficking of KCNE-K ؉ channel complexes give rise to disease. The cellular mechanisms responsible for ensuring that KCNE peptides assemble with voltage-gated K ؉ channels have yet to be elucidated. Using enzymatic deglycosylation, immunofluorescence, and quantitative cell surface labeling experiments, we show that KCNE1 peptides are retained in the early stages of the secretory pathway until they co-assemble with specific K ؉ channel subunits; co-assembly mediates KCNE1 progression through the secretory pathway and results in cell surface expression. We also address an apparent discrepancy between our results and a previous study in human embryonic kidney cells, which showed wild type KCNE1 peptides can reach the plasma membrane without exogenously expressed K ؉ channel subunits. By comparing KCNE1 trafficking in three cell lines, our data suggest that the errant KCNE1 trafficking observed in human embryonic kidney cells may be due, in part, to the presence of endogenous voltage-gated K ؉ channels in these cells.

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Section: Discussionmentioning

confidence: 53%

“…Two different studies suggest that Q1-E1 complex formation occurs at the plasma membrane, which would require both proteins to traffic through the secretory pathway independently (14,15). More recently, it was proposed that Q1-E1 assembly occurs in the ER because mutant E1 proteins could retain Q1 channels there (16).…”

mentioning

confidence: 99%

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

Chandrasekhar

Bas

Kobertz

2006

Journal of Biological Chemistry

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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.…”

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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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“…However, three novel Kcne (Kcne3, Kcne4, and Kcne5) family members have been recently reported, which are also widely distributed in the adult mouse (Grunnet et al, 2002(Grunnet et al, , 2003Teng et al, 2003). Coexpression experiments of Kcnq1 and Kcne3 subunits give rise to a constitutively opened pore (Mazhari et al, 2002), whereas coexpression with either Kcne4 or Kcne5 suppresses the current I Ks (Lundquist et al, 2005).…”

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confidence: 99%

Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development

2006

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Voltage-dependent potassium channels consist of a pore-forming ␣-subunit, which is modulated by additional ␤-ancillary or regulatory subunits. Kcnq1 and Kcnh2 ␣-channel subunits play pivotal roles in the developing and adult heart. However, Kcnq1 and Kcnh2 have a much wider expression profile than strictly confined to the myocardium, similar to their putative regulatory Kcne1-5 ␤-subunits. At present, the distribution of distinct potassium channel subunits has been partially mapped in adult tissues, whereas almost no information is available during embryonic development. In this study, we report a detailed analysis of Kcnq1, Kcnh2, and Kcne3 protein expression during mouse embryogenesis. Our results demonstrate that Kcnq1 and Kcnh2 are widely distributed. Coexpression of both ␣-subunits is observed in a wide variety of organs, such as heart and the skeletal muscle, whereas others display unique Kcnq1 or Knch2 expression. Interestingly, Kcne3 expression is also widely observed in distinct tissue layers during embryogenesis, supporting the notion that an exquisite balance of ␣-and ␤-subunit expression is required for modulating potassium conductance in distinct organs and tissue layers.

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KCNE4 is an inhibitory subunit to the KCNQ1 channel

Cited by 142 publications

References 36 publications

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

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

Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development

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KCNE4 is an inhibitory subunit to the KCNQ1 channel

Cited by 142 publications

References 36 publications

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

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

Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development

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