Inwardly rectifying K+ currents in intermediate cells in the cochlea of gerbils: a possible contribution to the endocochlear potential

Takeuchi, Shunji; Ando, Motonori

doi:10.1016/s0304-3940(98)00318-8

Cited by 46 publications

(46 citation statements)

References 16 publications

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“…We report that the Kir4.1 channel in the lateral wall resembles and has properties that are consistent with an intermediate inward rectifier channel. Furthermore, in contrast to the suggestion that the channel may confer high outward throughput of K ϩ across ICs into the IS in the StV (17,44), we propose that Kir4.1 in the ICs (16) may control the membrane potential of the cell and operate to reduce the K ϩ concentration in the IS. This action would serve to promote the steep K ϩ gradient necessary to generate EP.…”

Section: Kir41 In the Inner Earcontrasting

confidence: 82%

“…It has been demonstrated that the high throughput of K ϩ across ICs membrane yields EP (14,52,53). A combination of immunohistochemistry (16,54), pharmacological (44), and null mutant mice experiments (17) have resulted in the assertion that Kir4.1 channels residing at membranes of intermediate cells in the StV confer the extrusion of K ϩ to polarize the membrane. Marcus et al (17) noted the paradox that the present model possesses because of the inward rectification of the channel.…”

Section: Kir41 In the Inner Earmentioning

confidence: 99%

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Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Nie

Feng

Diaz

et al. 2005

Journal of Biological Chemistry

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L-␣-Difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials. Yet, the drug produces an across-frequency elevation of the hearing threshold, suggesting that DFMO may affect a common trait along the cochlear spiral. The mechanism for the ototoxic effects of DFMO remains uncertain. The cochlear duct is exclusively endowed with endocochlear potential (EP). EP is a requisite for normal sound transduction, as it provides the electromotive force that determines the magnitude of the receptor potential of hair cells. EP is generated by the high throughput of K ؉ across cells of the stria vascularis, conferred partly by the activity of Kir4.1 channels. Here, we show that the ototoxicity of DFMO may be mediated by alteration of the inward rectification of Kir4.1 channels, resulting in a marked reduction in EP. These findings are surprising given that the present model for EP generation asserts that Kir4.1 confers the outflow of K ؉ in the stria vascularis. We have proposed an alternative model. These findings should also enable the rational design of new pharmaceuticals devoid of the untoward effect of DFMO.

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Section: Kir41 In the Inner Earcontrasting

confidence: 82%

Section: Kir41 In the Inner Earmentioning

confidence: 99%

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Nie

Feng

Diaz

et al. 2005

Journal of Biological Chemistry

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“…In turn, lateral wall structures, in particular, the stria vascularis, are critical in maintaining ion homeostasis of the endolymph (Offner et al 1987;Salt et al 1987;Wangemann 1995;Wangemann et al 1995;Takeuchi and Ando 1998). The presence of Na/K-ATPases and Na/K/Cl cotransporters in the fibrocytes of the spiral ligament suggest that the ligament also plays a key role in the maintenance of the ionic environment and the endocochlear potential (Schulte and Adams 1989;Spicer and Schulte 1996;Crouch et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Lateral Wall Histopathology and Endocochlear Potential in the Noise-Damaged Mouse Cochlea

Hirose

Liberman

2003

JARO - Journal of the Association for Research in Otolaryngolog

247

221

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Noise exposure damages the stria and spiral ligament and may contribute to noise-induced threshold shift by altering the endocochlear potential (EP). The aim of this study was to correlate lateral wall histopathology with changes in EP and ABR thresholds. CBA/CaJ mice were exposed to octave band (8-16 kHz) noise for 2 h at intensities ranging from 94 to 116 dB SPL and evaluated 0 h to 8 weeks postexposure. EP in control mice averaged 86 and 101 mV in apical and basal turns, respectively. The 94 dB exposures caused a 40 dB temporary threshold shift (TTS), and there was with no corresponding change in EP. The 112 and 116 dB exposures caused >60 dB threshold shifts at 24 h, and EP was transiently decreased, e.g., to 21 and 27 mV in apical and basal turns after 116 dB. By 1 week postexposure, EP returned to control values in all exposure groups, although those exposed to 112 or 116 dB showed large permanent threshold shifts (PTS). Cochleas were plastic-embedded and serialsectioned for light microscopic and ultrastructural analysis. Acute changes included degeneration of type II fibrocytes of the spiral ligament and strial edema. The strial swelling peaked at 24 h when significant EP recovery had taken place, suggesting that these changes reflect compensatory volume changes. In the chronic state, massive loss of type II fibrocytes and degeneration of strial intermediate and marginal cells was observed with drastic reduction in membrane surface area. The results suggest that EP shifts do not occur with TTS and also do not add significantly to PTS in the steady state. However, EP loss could contribute to acute threshold shifts that resolve to a PTS. EP recovery despite significant strial degeneration may be partly due to decreased transduction current caused by hair cell damage.

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“…Potassium is transported out of the IS space and into the marginal cells (MC) of the StV by a 1 -Na,K-ATPase in conjunction with Na-K-2Cl co-transporter (NKCC1), both located on the MC basolateral membrane (Offner et al 1987;Salt and DeMott 1999). K + secretion into the endolymph is completed via KCNQ1 in MC apical membranes (Casimiro et al 2004;Lee et al 2000;Takeuchi and Ando 1998;Takeuchi et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Conservation of Hearing by Simultaneous Mutation of Na,K-ATPase and NKCC1

Diaz

Vázquez

Dou

et al. 2007

JARO

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Although drug-induced and age-related hearing losses are frequent otologic problems affecting millions of people, their underlying mechanisms remain uncertain. The inner ear is exclusively endowed with a positive endocochlear potential (EP) that serves as the main driving force for the generation of receptor potential in hair cells to confer hearing. Deterioration of EP leads to hearing loss or deafness. The generation of EP relies on the activity of many ion transporters to establish active potassium (K + ) cycling within the inner ear, including K + channels, the Na-K-2Cl co-transporter (NKCC1), and the a 1 and a 2 isoforms of Na,K-ATPase. We show that heterozygous deletion of either NKCC1, a 1 -Na,K-ATPase, or a 2 -Na,K-ATPase independently results in progressive, age-dependent hearing loss with minimal alteration in cochlear morphology. Double heterozygote deletion of NKCC1 with a 1 -Na,K-ATPase also shows a progressive, though delayed, age-dependent hearing loss. Remarkably, double heterozygote deletion of NKCC1 with a 2 -Na,K-ATPase demonstrates a striking preservation of hearing threshold both initially and with age. Measurements of the EP confirm the anticipated drop in potential for genotypes that demonstrate age-dependent hearing loss. The EP generated by the NKCC1 + a 2 -Na,K-ATPase double heterozygote, however, is maintained at a level comparable to that of the control condition, suggesting a potential advantage in this combination of ion transporter modification. These observations provide insight into the detailed mechanisms of EP generation, and results of combination-knockout experiments may have important implications in the future treatment of drug-induced and age-related hearing losses.

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Inwardly rectifying K+ currents in intermediate cells in the cochlea of gerbils: a possible contribution to the endocochlear potential

Cited by 46 publications

References 16 publications

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Lateral Wall Histopathology and Endocochlear Potential in the Noise-Damaged Mouse Cochlea

Conservation of Hearing by Simultaneous Mutation of Na,K-ATPase and NKCC1

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