Resting Potential and Submembrane Calcium Concentration of Inner Hair Cells in the Isolated Mouse Cochlea Are Set by KCNQ-Type Potassium Channels

Oliver, Dominik; Knipper, Marlies; Derst, Christian; Fakler, Bernd

doi:10.1523/jneurosci.23-06-02141.2003

Cited by 136 publications

(222 citation statements)

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“…However, normal hearing function up to age 4 weeks indicates that graded receptor potentials are possible without BK␣. Recently, evidence was presented for the presence of KCNQ4 channels in IHCs (16,30). Although KCNQ4 provides a small maximum conductance, it is activated at the resting potential to Ϸ75%, which adds substantially to the total K ϩ conductance around the resting potential, thereby contributing to a graded receptor potential.…”

Section: Bk␣ Deletion Leads To Hearing Loss Despite Normal Phenotypes Ofmentioning

confidence: 99%

“…Besides hearing measurements, the phenotype of the cochlea was studied by using markers for efferent (13) and afferent fibers (14). The integrity of IHCs and OHCs in adult mice was evaluated by assessing the expression of KCNQ4 (15,16). Expression of the postsynaptic Ca 2ϩ -dependent potassium channel SK2, which transduces specific responses of efferent neurons to OHCs (17), and the motor protein prestin (18,19) was examined to prove a normal OHC phenotype.…”

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confidence: 99%

“…Cochleae were isolated, dissected, fixed, cryosectioned, and stained as described (16,22,23). Anti-BK␣ (polyclonal anti-rabbit, Alomone Labs, Jerusalem; APC-021) and anti-BK␣ polyclonal antibody, recently generated (25), were used with similar results.…”

mentioning

confidence: 99%

“…The cochlear duct was prepared, segmented, and stained with rabbit anti-KCNQ4, rabbit anti-BK, and sheep anti-synaptophysin. Images were obtained by using a confocal laser-scanning microscope (Zeiss LSM 510), as described (16). …”

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Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Rüttiger

Sausbier

Zimmermann

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The large conductance voltage-and Ca 2؉ -activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming ␣-subunit coexpressed with the auxiliary ␤1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel ␣-(BK␣ ؊/؊ ) and ␤1-subunit (BK␤1 ؊/؊ ) knockout mice, we demonstrate normal hearing function and cochlear structure of BK␤1 ؊/؊ mice. During the first 4 postnatal weeks also, BK␣ ؊/؊ mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BK␣ ؊/؊ mice only from Ϸ8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations.cochlea ͉ KCNQ4 C a 2ϩ -activated potassium (BK) channels are heterooctamers of four ␣-and four ␤-subunits. The pore-forming ␣-subunit (KCNMA1) is a member of the slo family of potassium channels (1), originally identified in Drosophila (2). Studies of BK channels from smooth muscle have identified an auxiliary ␤1-subunit (KCNMB1) whose presence in the channel complex confers an increased voltage and calcium sensitivity toward the poreforming ␣-subunit (3).In turtle and chick, there is evidence that differential splicing of the BK channel ␣-subunit in conjunction with a graded expression of the auxiliary ␤-subunit along the tonotopic axis provides the functional heterogeneity of BK channels that underlies electrical tuning (for review, see ref. 4).In inner hair cells (IHCs) of the mammalian organ of Corti, the predominant K ϩ conductance is a voltage-and Ca 2ϩ -activated K ϩ channel termed I K,f (5, 6). BK channel mRNA (7,8) and protein expression (8) were shown in IHCs, indicating that I K,f flows through BK channels. The presumed physiological roles of BK channels are (i) a decrease of the membrane time constant even at the resting potential and (ii) fast repolarization of the receptor potential. Both contribute to phase-locked receptor potentials up to high sound frequencies (6). In addition to IHCs, BK type Ca 2ϩ -activated K ϩ conductances have been measured in OHCs (9) and in efferent fibers onto outer hair cells (OHCs) (10). The role of BKs in either OHCs or efferents is still controversially discussed (9).Studying the expression of BK channel ␣-splice variants and ␤-isoforms in rat cochlea using in situ hybridization and PCR techniques revealed the strict coexpressio...

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Section: Bk␣ Deletion Leads To Hearing Loss Despite Normal Phenotypes Ofmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Rüttiger

Sausbier

Zimmermann

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…I K,n is also present in adult inner hair cells (IHCs). It is developmentally regulated and contributes only to mouse IHCs' resting membrane potential from P19 onward (Marcotti et al 2003;Oliver et al 2003). I K,n can be blocked by linopirdine with an IC 50 near 1 lM (Marcotti and Kros 1999); therefore, cholinergic effects might be better studied in the presence of this compound.…”

Section: Introductionmentioning

confidence: 99%

Linopirdine Blocks α9α10-Containing Nicotinic Cholinergic Receptors of Cochlear Hair Cells

Gómez-Casati

Katz

Glowatzki

et al. 2004

JARO

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Studies of the electrophysiological response to acetylcholine (ACh) in mammalian outer hair cells (OHCs) are hindered by the presence of a large potassium current, I K,n , most likely mediated by channels containing the KCNQ4 subunit. Since I K,n can be blocked by linopirdine, cholinergic effects might be better revealed in the presence of this compound. The aim of the present work was to study the effects of linopirdine on the ACh-evoked responses through a9a10-containing native and recombinant nicotinic cholinergic receptors. Responses to ACh were blocked by linopirdine in both OHCs and inner hair cells (IHCs) of rats at postnatal days 21-27 (OHCs) and 9-11 (IHCs). In addition, linopirdine blocked responses of recombinant a9a10 nicotinic cholinergic receptors (nAChRs) in a concentrationdependent manner with an IC 50 of 5.2 lM. Block by linopirdine was readily reversible, voltage independent, and surmountable at high concentrations of ACh, thus suggestive of a competitive type of interaction with the receptor. The present results contribute to the pharmacological characterization of a9a10-containing nicotinic receptors and indicate that linopirdine should be used with caution when analyzing the cholinergic sensitivity of cochlear hair cells.

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Inner hair cell Cre‐expressing transgenic mouse

Tian

Fritzsch

et al. 2004

Genesis

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Cochlear hair cells of the inner ear are mechanosensory transducers critical for sound reception in mammals. A mouse with a specific expression of Cre recombinase activity in hair cells is essential for hair cell-specific gene targeting. Here we report a transgenic mouse in which Cre activity is detected in inner hair cells, not in supporting cells, in the cochlea. The Cre activity was visualized with both X-gal staining and beta-galactosidase immunostaining in progeny of a cross between our Cre line and the reporter ROSA26R line. In inner hair cells, the Cre activity started at postnatal day 14 and was maintained throughout adulthood. Starting at postnatal day 50, a few outer hair cells in the outermost row of cochlear apical and middle turns displayed the Cre activity. In vestibular hair cells and spiral ganglia, the Cre activity was also detected. Cre activity was present in cells widely distributed throughout brain, testis, and retina, but was absent in many other tissues such as kidney, heart, liver, and intestine. This Cre mouse line can thus be used for conditional gene targeting in mature inner hair cells of the cochlea. genesis 39:173-177, 2004.

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Resting Potential and Submembrane Calcium Concentration of Inner Hair Cells in the Isolated Mouse Cochlea Are Set by KCNQ-Type Potassium Channels

Cited by 136 publications

References 39 publications

Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Linopirdine Blocks α9α10-Containing Nicotinic Cholinergic Receptors of Cochlear Hair Cells

Inner hair cell Cre‐expressing transgenic mouse

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Resting Potential and Submembrane Calcium Concentration of Inner Hair Cells in the Isolated Mouse Cochlea Are Set by KCNQ-Type Potassium Channels

Cited by 136 publications

References 39 publications

Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Linopirdine Blocks α9α10-Containing Nicotinic Cholinergic Receptors of Cochlear Hair Cells

Inner hair cell Cre‐expressing transgenic mouse

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Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

Deletion of the Ca²+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss