Dominant-Negative Inhibition of M-Like Potassium Conductances in Hair Cells of the Mouse Inner Ear

Holt, Jeffrey R.; Stauffer, Eric A.; Abraham, David; Géléoc, Gwenaëlle S. G.

doi:10.1523/jneurosci.2085-07.2007

Cited by 58 publications

(65 citation statements)

References 41 publications

(87 reference statements)

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“…Previous studies have suggested that in the inner ear the K v 7.4 channel is highly expressed in IHC and outer hair cells (4). Because K v 7 channel-mediated currents are activated at low membrane voltages, it has been suggested and demonstrated that K v 7.4 currents contribute substantially in establishing V rest of IHCs and, in so doing, control intracellular Ca 2ϩ concentrations (15,16). Although not demonstrated either in vitro or in vivo, the implications of these findings are that a pathological rise in intracellular Ca 2ϩ may ensue due to reduced expression or dysfunction of K v 7.4 in DFNA2, leading to cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, determination of the properties of native K v 7 channels may be obscured by regulation of KCNE subunits (41) and the ␣-subunit interaction with K v 10.1 (ERG1) (42)(43)(44). Thus, null deletion of one subtype of K v 7 channels may produce a modest phenotype (39), but a dominant negative version of a K v 7.4 channel subunit will impair the entire K ϩ channel class, resulting in a profound auditory phenotype (16,20).…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps most puzzlingly is why degeneration of hair cells apparently precedes SGNs because they also express K v 7.4 and K v 7 channel subtypes (7,14). Because K v 7 channels are activated at low membrane voltages (approximately -80 mV), they contribute substantially in establishing the resting membrane voltage (V rest ) of IHCs and, in doing so, control intracellular Ca 2ϩ concentration (15,16). To determine the roles of K v 7 channel currents in SGNs and to identify the potential cellular mechanisms for K v 7.4 mutationassociated degeneration of these neurons, we surmised that in DFNA2 loss of SGNs may occur independent of hair cell loss.…”

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confidence: 99%

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Kv7-type Channel Currents in Spiral Ganglion Neurons

Wei

Yamoah

2010

Journal of Biological Chemistry

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Alterations in K v 7-mediated currents in excitable cells result in several diseased conditions. A case in DFNA2, an autosomal dominant version of progressive hearing loss, involves degeneration of hair cells and spiral ganglion neurons (SGNs) from basal to apical cochlea, manifesting as high-to-low frequency hearing loss, and has been ascribed to mutations in K v 7.4 channels. Analyses of the cellular mechanisms of K v 7.4 mutations and progressive degeneration of SGNs have been hampered by the paucity of functional data on the role K v 7 channels play in young and adult neurons. To understand the cellular mechanisms of the disease in SGNs, we examined temporal (young, 0.5 months old, and senescent, 17 months old) and spatial (apical and basal) roles of K v 7-mediated currents. We report that differential contribution of K v 7 currents in mice SGNs results in distinct and profound variations of the membrane properties of basal versus apical neurons. The current produces a major impact on the resting membrane potential of basal neurons. Inhibition of the current promotes membrane depolarization, resulting in activation of Ca 2؉ currents and a sustained rise in intracellular Ca 2؉ . Using TUNEL assay, we demonstrate that a sustained increase in intracellular Ca 2؉ mediated by inhibition of K v 7 current results in significant SGN apoptotic death. Thus, this study provides evidence of the cellular etiology and mechanisms of SGN degeneration in DFNA2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Kv7-type Channel Currents in Spiral Ganglion Neurons

Wei

Yamoah

2010

Journal of Biological Chemistry

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“…I K,L confers more hyperpolarized resting potentials to type I hair cells. However, Holt et al (2007) concluded that loss of I K,L in type I hair cells did not depolarize the cells' resting potential to the extent expected, because in the absence of I K,L , persistent I K1 may compensate. Figure 1, B and D, shows mean steady-state I(V) curves from type II cells at the same ages shown in Fig.…”

Section: Inward Rectifier Currents In Utricle Hair Cellsmentioning

confidence: 95%

The function and molecular identity of inward rectifier channels in vestibular hair cells of the mouse inner ear

Levin

Holt

2012

Journal of Neurophysiology

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Inner ear hair cells respond to mechanical stimuli with graded receptor potentials. These graded responses are modulated by a host of voltage-dependent currents that flow across the basolateral membrane. Here, we examine the molecular identity and the function of a class of voltage-dependent ion channels that carries the potassium-selective inward rectifier current known as IK1. IK1has been identified in vestibular hair cells of various species, but its molecular composition and functional contributions remain obscure. We used quantitative RT-PCR to show that the inward rectifier gene, Kir2.1, is highly expressed in mouse utricle between embryonic day 15 and adulthood. We confirmed Kir2.1 protein expression in hair cells by immunolocalization. To examine the molecular composition of IK1, we recorded voltage-dependent currents from type II hair cells in response to 50-ms steps from −124 to −54 in 10-mV increments. Wild-type cells had rapidly activating inward currents with reversal potentials close to the K+equilibrium potential and a whole-cell conductance of 4.8 ± 1.5 nS ( n = 46). In utricle hair cells from Kir2.1-deficient (Kir2.1−/−) mice, IK1was absent at all stages examined. To identify the functional contribution of Kir2.1, we recorded membrane responses in current-clamp mode. Hair cells from Kir2.1−/−mice had significantly ( P < 0.001) more depolarized resting potentials and larger, slower membrane responses than those of wild-type cells. These data suggest that Kir2.1 is required for IK1in type II utricle hair cells and contributes to hyperpolarized resting potentials and fast, small amplitude receptor potentials in response to current inputs, such as those evoked by hair bundle deflections.

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“…The M-channel has been implicated also in the neurogenesis of tinnitus (Holt et al, 2007). In the current study the EC 50 of linopirdine was 176 μM, which is approaching a physiological range and may thus serve as an adjunctive therapy for tinnitus, but would have to be made available once again to the consumer market.…”

Section: Discussionmentioning

confidence: 69%

An in vitro model for testing drugs to treat tinnitus

Gopal

Gross

et al. 2011

European Journal of Pharmacology

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Pregabalin Gabapentin Drug repositioningTinnitus affects approximately 50 million people in the USA alone, with 10 million being highly debilitated. Pharmacotherapy for tinnitus is still in emerging stages due to time consuming clinical trials and/or animal experiments. We tested a new cellular model where induced rapid neuronal firing or spiking was used as a mimic for the type of aberrant activity that may occur in tinnitus. Spontaneously active auditory cortical networks growing on microelectrode arrays were exposed to pentylenetetrazol (PTZ), a proconvulsant and an antagonist of GABA A receptor, which is implicated in tinnitus. Auditory cortical networks were then exposed to experimental tinnitus drugs linopirdine (Dup966, a potassium channel blocker), L-carnitine (an antioxidant), or selective Ca 2+ channel antagonists pregabalin (Lyrica), or gabapentin (Neurontin) at various concentrations. PTZ increased spike rate by 139.6 ± 27% and burst rate by 129.7 ± 28% in auditory cortical networks with a phenotypic high firing of excitable neurons. Reductions of increased activity were observed to varying degrees using the experimental tinnitus drugs. The potency of the drugs was linopirdine (EC 50 : 176±7.0 μM) N L-carnitine (EC 50 : 1569± 41 μM)N pregabalin (EC 50 : 8360± 340 μM), Ngabapentin, with 34.2± 7.5% efficacy (EC 50 : 2092± 980 μM). These studies provide proof of principle for the use of auditory cortical networks on microelectrode array as a feasible platform for semi-high throughput application for screening of drugs that might be used for the treatment of tinnitus.

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Dominant-Negative Inhibition of M-Like Potassium Conductances in Hair Cells of the Mouse Inner Ear

Cited by 58 publications

References 41 publications

Kv7-type Channel Currents in Spiral Ganglion Neurons

Kv7-type Channel Currents in Spiral Ganglion Neurons

The function and molecular identity of inward rectifier channels in vestibular hair cells of the mouse inner ear

An in vitro model for testing drugs to treat tinnitus

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