Contribution of BK Ca2+-Activated K+Channels to Auditory Neurotransmission in the Guinea Pig Cochlea

Skinner, Liam J.; Enee, Véronique; Beurg, Maryline; Jung, Hak Hyun; Ryan, Allen F.; Hafidi, Aziz; Aran, Jean‐Marie; Dulon, Didier

doi:10.1152/jn.01155.2002

Cited by 75 publications

(70 citation statements)

References 44 publications

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“…Spontaneous firing develops also in injured myelinated afferents after SNL [53], thus our findings that axotomized myelinated -but not adjacent uninjured afferents-develop increased excitability, and axotomized medium-sized fibers lose I K(Ca) , contribute additional support to the argument that injured (and not uninjured) myelinated afferents mediate neuropathic pain behavior after SNL [6]. Because BK channels control neurotransmitter release [86] and inter-neuronal glutaminergic synaptic efficacy [72], it is also likely that loss of BK currents in small and medium sized neurons after axotomy may enhance synaptic transmission of afferent signaling, as well. In addition to loss of I K(Ca) currents in a manner directly related to nerve injury, we have also previously shown that neuropathy decreases I Ca [60,61], a mechanism that may reduce the activation of K (Ca) currents in addition to the direct effect of SNL, thus leading to a higher enhancement of excitability.…”

Section: Discussionsupporting

confidence: 61%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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Calcium-activated potassium channels regulate AHP and excitability in neurons. Since we have previously shown that axotomy decreases I Ca in DRG neurons, we investigated the association between I Ca and K (Ca) currents in control medium-sized (30-39 μM) neurons, as well as axotomized L5 or adjacent L4 DRG neurons from hyperalgesic rats following L5 SNL. Currents in response to AP waveform voltage commands were recorded first in Tyrode's solution and sequentially after: 1) blocking Na + current with NMDG and TTX; 2) addition of K (Ca) blockers with a combination of apamin 1μM, iberiotoxin 200 nM, and clotrimazole 500 nM; 3) blocking remaining K + current with the addition of 4-AP, TEA-Cl, and glibenclamide; and 4) blocking I Ca with cadmium. In separate experiments, currents were evoked (HP −60 mV, 200 ms square command pulses from −100 to +50 mV) while ensuring high levels of activation of I K(Ca) by clamping cytosolic Ca 2+ concentration with pipette solution in which Ca 2+ was buffered to1μM. This revealed I K(Ca) with components sensitive to apamin, clotrimazole and iberiotoxin. SNL decreases total I K(Ca) in axotomized (L5) neurons, but increases total I K(Ca) in adjacent (L4) DRG neurons. All I K(Ca) subtypes are decreased by axotomy, but iberiotoxin-sensitive and clotrimazole-sensitive current densities are increased in adjacent L4 neurons after SNL. In an additional set of experiments we found that small sized control DRG neurons also expressed iberiotoxin-sensitive currents, which are reduced in both axotomized (L5) and adjacent (L4) neurons.Conclusions: Axotomy decreases I K(Ca) due to a direct effect on K (Ca) channels. Axotomy-induced loss of I Ca may further potentiate current reduction. This reduction in I K(Ca) may contribute to elevated excitability after axotomy. Adjacent neurons (L4 after SNL) exhibit increased I K(Ca) current.

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Section: Discussionsupporting

confidence: 61%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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“…BK channels were shown to be present in the stria vascularis by immunocytochemistry (8) and electrophysiology (28) as well as in fibrocytes of the spiral ligament by electrophysiology (29). Although we cannot exclude effects on the endocochlear potential in BK␣ Ϫ/Ϫ mice older than those studied here, we were unable to detect any phenotypical change in the stria vascularis in BK␣ Ϫ/Ϫ mice, in line with the described profile of hearing loss.…”

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

confidence: 52%

“…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.…”

mentioning

confidence: 99%

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.

182

160

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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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“…Indeed, acute blockade of the BK␣ subunit by perfusion of the BK channel blocker iberiotoxin into the guinea pig cochlea reduces the auditory nerve compound action potential (21), suggesting that compensatory mechanisms may be responsible for the normal hearing we observe in mice genetically designed to lack the BK␣ subunit at all developmental stages. Moreover, this compensation could occur in cells of the cochlea other than the IHCs.…”

Section: Regulation Of Other Gene Products Does Not Compensate For Thmentioning

confidence: 98%

“…IHCs express a potassium current (termed I K,f ) pharmacologically similar to BK currents, showing sensitivity to low concentrations of tetraethylammonium, charybdotoxin, and iberiotoxin (17)(18)(19)(20)(21). The transcript for the BK␣ subunit has been detected in IHCs (22,23), and immunostaining has verified expression of the BK␣ subunit in IHCs (17,20,21,24). Additionally, transcripts for both the BK␤1 and ␤4 subunit have been identified in IHCs (22).…”

mentioning

confidence: 99%

Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

Pyott

Meredith

Fodor

et al. 2007

Journal of Biological Chemistry

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Large conductance voltage-and calcium-activated potassium (BK) channels are important for regulating many essential cellular functions, from neuronal action potential shape and firing rate to smooth muscle contractility. In amphibians, reptiles, and birds, BK channels mediate the intrinsic frequency tuning of the cochlear hair cell by an electrical resonance mechanism. In contrast, inner hair cells of the mammalian cochlea are extrinsically tuned by accessory structures of the cochlea. Nevertheless, BK channels are present in inner hair cells and encode a fast activating outward current. To understand the role of the BK channel ␣ and ␤ subunits in mammalian inner hair cells, we analyzed the morphology, physiology, and function of these cells from mice lacking the BK channel ␣ (Slo ؊/؊ ) and also the ␤1 and ␤4 subunits (␤1/4 ؊/؊ ). ␤1/4 ؊/؊ mice showed normal subcellular localization, developmental acquisition, and expression of BK channels. ␤1/4 ؊/؊ mice showed normal cochlear function as indicated by normal auditory brainstem responses and distortion product otoacoustic emissions. Slo ؊/؊ mice also showed normal cochlear function despite the absence of the BK␣ subunit and the absence of fast activating outward current from the inner hair cells. Moreover, microarray analyses revealed no compensatory changes in transcripts encoding ion channels or transporters in the cochlea from Slo ؊/؊ mice. Slo ؊/؊ mice did, however, show increased resistance to noise-induced hearing loss. These findings reveal the fundamentally different contribution of BK channels to nonmammalian and mammalian hearing and suggest that BK channels should be considered a target in the prevention of noise-induced hearing loss.

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Contribution of BK Ca²⁺-Activated K⁺Channels to Auditory Neurotransmission in the Guinea Pig Cochlea

Cited by 75 publications

References 44 publications

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

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

Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

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Contribution of BK Ca2+-Activated K+Channels to Auditory Neurotransmission in the Guinea Pig Cochlea

Cited by 75 publications

References 44 publications

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

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

Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

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Contribution of BK Ca²⁺-Activated K⁺Channels to Auditory Neurotransmission in the Guinea Pig Cochlea

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