Kv7-type Channel Currents in Spiral Ganglion Neurons

Lv, Ping; Wei, Daoyan; Yamoah, Ebenezer N.

doi:10.1074/jbc.m110.136192

Cited by 56 publications

(47 citation statements)

References 45 publications

(56 reference statements)

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“…In the auditory nerve, neurons are tonotopically organized, where position-dependent changes in frequency encoding accompany differences in potassium channel distribution and firing patterns (Adamson et al, 2002; Lv et al, 2010). In this study, combining an induced genetic cue with neurotrophin exposure yielded stem cell-derived neurons with distinct passive electrical properties and voltage-gated potassium channel expression.…”

Section: Discussionmentioning

confidence: 99%

BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells

Purcell¹,

Yang²,

Liu³

et al. 2013

Stem Cell Research

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Neurons resembling the spiral ganglion neurons (SGNs) of the auditory nerve can be generated from embryonic stem cells through induced over-expression of the transcription factor Neurogenin-1 (Neurog1). While recapitulating this developmental pathway produces glutamatergic, bipolar neurons reminiscent of SGNs, these neurons are functionally immature, being characterized by a depolarized resting potential and limited excitability. We explored the effects of two neurotrophins known to be present in the inner ear, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), on the electrophysiology of neurons following Neurog1-induction. Our data reveal a significant reduction in resting membrane potential (RMP) following neurotrophin exposure, with BDNF producing a more robust effect than NT-3. This effect was accompanied by a profound and specific upregulation of the KCNQ4 subtype, where a 9-fold increase was observed with quantitative PCR. The other neuronally-expressed KCNQ subtypes (2, 3, and 5) exhibited upregulation which was 3-fold or less in magnitude. Quantitative immunohistochemistry confirmed the increase in KCNQ4 expression at the protein level. The present data show a novel link between BDNF and KCNQ4 expression, yielding insight into the restricted expression pattern of a channel known to play a special roles in setting the resting potential of auditory cells and in the etiology of progressive high frequency hearing loss.

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Section: Discussionmentioning

confidence: 99%

BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells

Purcell¹,

Yang²,

Liu³

et al. 2013

Stem Cell Research

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“…The M-current, the phenotypic current derived from Kv7 channels, dictates the resting potential of hair cells and spiral ganglion neurons (7), and it is expected that reduction in the current magnitude in disease conditions will confer membrane depolarization, resulting in increased excess intracellular Ca 2ϩ and Ca 2ϩ -induced cell death (6,7,28). The progressive nature of the disease may reflect age-induced reduction in expression of the channels.…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Kim

Sihn

2011

Journal of Biological Chemistry

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Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K ؉ channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded nonfunctional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2.

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“…Kv7 channels underlie the neuronal M current and are constituents of the low voltage-activated K ϩ channels in auditory and vestibular HCs and neurons, where they enhance temporal fidelity and control the regularity of trains of spikes to sculpt the coding of information (39,42,47,48). Here we demonstrate that CaM binds to two different isoforms of hKv7.4 channel in a Ca 2ϩ -independent manner but that only the long isoform (Kv7.4a) is down-regulated by CaM.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels

Sihn

Kim²,

Woltz³

et al. 2016

Journal of Biological Chemistry

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Calmodulin (CaM), a Ca2؉ -sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca 2؉ -dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report that CaM binds to two isoforms of the hKv7.4 channel in a Ca 2؉ -independent manner but that only the long isoform (hKv7.4a) is regulated by Ca 2؉ /CaM. Ca 2؉ /CaM mediate reduction of the hKv7.4a channel by decreasing the channel open probability and altering activation kinetics. We took advantage of a known missense mutation (G321S) that has been linked to progressive hearing loss to further examine the inhibitory effects of Ca 2؉ / CaM on the Kv7.4 channel. Using multidisciplinary techniques, we demonstrate that the G321S mutation may destabilize CaM binding, leading to a decrease in the inhibitory effects of Ca 2؉ on the channels. Our study utilizes an expression system to dissect the biophysical properties of the WT and mutant Kv7.4 channels. This report provides mechanistic insights into the critical roles of Ca 2؉ /CaM regulation of the Kv7.4 channel under physiological and pathological conditions.

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Kv7-type Channel Currents in Spiral Ganglion Neurons

Cited by 56 publications

References 45 publications

BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells

BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels

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