The selectivity of the hair cell’s mechanoelectrical-transduction channel promotes Ca
            <sup>2+</sup>
            flux at low Ca
            <sup>2+</sup>
            concentrations

Lumpkin, Ellen A.; Marquis, Robert E.; Hudspeth, A. J.

doi:10.1073/pnas.94.20.10997

Cited by 81 publications

(50 citation statements)

References 40 publications

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“…Transduction is initiated by deflection of the hair bundle, the mechanosensory organelle (Hudspeth, 1989). Bundle deflection directly gates the transduction channel, allowing a substantial influx of Ca 2ϩ (Lumpkin et al, 1997;Ricci and Fettiplace, 1998), which is critical for bundle function (Lenzi and Roberts, 1994). Bundles not only are bathed in endolymph, a K ϩ -rich extracellular fluid that cannot support Na ϩ /Ca 2ϩ exchange, but they also have no intracellular compartments that could sequester Ca 2ϩ (Jacobs and Hudspeth, 1990).…”

Section: Introductionmentioning

confidence: 99%

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Hill

Williams

LeMasurier

et al. 2006

Journal of Neuroscience

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Localization of mechanotransduction in sensory hair cells to hair bundles requires selective targeting of essential proteins to specific locations. Isoform 2 of the plasma-membrane Ca 2ϩ -ATPase (PMCA2), required for hearing and balance, is found exclusively in hair bundles. We determined the contribution of splicing at the two major splicing sites (A and C) to hair-cell targeting of PMCA2. When PMCA2 isoforms were immunoprecipitated from purified hair bundles of rat utricle, 2w was the only site A variant detected; moreover, immunocytochemistry for 2w in rat vestibular and cochlear tissues indicated that this splice form was located solely in bundles. To demonstrate the necessity of the 2w sequence, we transfected hair cells with PMCA2 containing different variants at splice sites A and C. Although native hair bundles exclusively use the 2a form at splice-site C, epitope-tagged PMCA2w/a and PMCA2w/b were both concentrated in bundles, indicating that site C is not involved in bundle targeting. In contrast, PMCA2z/a was excluded from bundles and was instead targeted to the basolateral plasma membrane. Bundle-specific targeting of PMCA2w/a tagged with green fluorescent protein (GFP) was diminished, suggesting that GFP interfered with splice-site A. Together, these data demonstrate that PMCA2w/a is the hairbundle isoform of PMCA in rat hair cells and that 2w targets PMCA2 to bundles. The 2w sequence is thus the first targeting signal identified for a hair-bundle membrane protein; moreover, the striking distribution of inner-ear PMCA isoforms dictated by selective targeting suggests a critical functional role for segregated pathways of Ca 2ϩ transport.

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Section: Introductionmentioning

confidence: 99%

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Hill

Williams

LeMasurier

et al. 2006

Journal of Neuroscience

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“…Endolymphatic fluid surrounds the stereocilia and apical surface of hair cells. Sound causes deflection of stereocilia that, when directed towards the tallest stereocilium, opens cation-selective transduction channels, allowing endolymph potassium (K + ) and calcium (Ca 2+ ) to flow into and depolarize the hair cells (Lumpkin et al 1997;Ricci and Fettiplace 1998).…”

Section: Introductionmentioning

confidence: 99%

Low Endolymph Calcium Concentrations in deafwaddler2J Mice Suggest that PMCA2 Contributes to Endolymph Calcium Maintenance

Wood

Muchinsky

Filoteo

et al. 2004

JARO

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In vertebrates, transduction of sound into an electrochemical signal is carried out by hair cells that rely on calcium to perform specialized functions. The apical surfaces of hair cells are surrounded by endolymphatic fluid containing calcium at concentrations that must be maintained by active transport. The mechanism of this transport is unknown, but an ATPdependent pump is believed to participate. Mutation of the Atp2b2 gene that encodes plasma membrane calcium ATPase type 2 (PMCA2) produces the deaf, ataxic mouse: deafwaddler 2J (dfw 2J ). We hypothesized that PMCA2 might transport calcium into the endolymph and that dfw 2J mice would have low endolymph calcium concentrations, possibly contributing to their deafness and ataxia. First, using immunocytochemistry, we demonstrated that PMCA2 is present in control mice inner and outer hair cell stereocilia where it could pump calcium into the endolymph and that PMCA2 is absent in dfw 2J stereocilia. Second, using an aspirating microelectrode and calcium-sensitive fluorescent dye, we found that dfw 2J mice endolymph calcium concentrations are significantly lower than those of control mice. These findings suggest that PMCA2, located in hair cell stereocilia, contributes significantly to endolymph calcium maintenance.

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“…MET current amplitude is increased because of high permeability of K ϩ through transduction channels relative to other monovalent ions (Ohmori, 1985;Farris et al, 2004). K ϩ promotes Ca 2ϩ permeation through the channel, likely through anomalous mole fraction behavior (Lumpkin et al, 1997;. A significant portion of MET current, 10 -20%, is carried by Ca 2ϩ when the bundle is exposed to [Ca 2ϩ ] Ͻ 100 M (Lumpkin et al, 1997; .…”

Section: What Is [Ca 2؉ ] Of Turtle Endolymph?mentioning

confidence: 99%

“…Calcium blocks the channel with a half blocking dose of 1 mM . Calcium also permeates the channel in which it modulates at least two forms of MET adaptation (Ohmori, 1985;Crawford et al, 1989Crawford et al, , 1991Lumpkin et al, 1997;Wu et al, 1999). Complicating interpretation of bulk endolymph Ca 2ϩ concentrations is the high density of Ca 2ϩ ATPases in the stereocilia, which may create an increasing [Ca 2ϩ ] gradient near the MET channel and thus make a more localized [Ca 2ϩ ] estimate essential Yamoah et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Steady-State Adaptation of Mechanotransduction Modulates the Resting Potential of Auditory Hair Cells, Providing an Assay for Endolymph [Ca²⁺]

Farris¹,

Wells²,

Ricci³

2006

J. Neurosci.

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The auditory hair cell resting potential is critical for proper translation of acoustic signals to the CNS, because it determines their filtering properties, their ability to respond to stimuli of both polarities, and, because the hair cell drives afferent firing rates, the resting potential dictates spontaneous transmitter release. In turtle auditory hair cells, the filtering properties are established by the interactions between BK calcium-activated potassium channels and an L-type calcium channel (electrical resonance). However, both theoretical and in vitro recordings indicate that a third conductance is required to set the resting potential to a point on the I Ca and I BK activation curves in which filtering is optimized like that found in vivo. Present data elucidate a novel mechanism, likely universal among hair cells, in which mechanoelectric transduction (MET) and its calcium-dependent adaptation provide the depolarizing current to establish the hair cell resting potential. First, mechanical block of the MET current hyperpolarized the membrane potential, resulting in broadband asymmetrical resonance. Second, altering steady-state adaptation by altering the [Ca 2ϩ ] bathing the hair bundle changed the MET current at rest, the magnitude of which resulted in membrane potential changes that encompassed the best resonant voltage. The Ca 2ϩ sensitivity of adaptation allowed for the first physiological estimate of endolymphatic Ca 2ϩ near the MET channel (56 Ϯ 11 M), a value similar to bulk endolymph levels. These effects of MET current on resting potential were independently confirmed using a theoretical model of electrical resonance that included the steady-state MET conductance.

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The selectivity of the hair cell’s mechanoelectrical-transduction channel promotes Ca ²⁺ flux at low Ca ²⁺ concentrations

Abstract: The mechanoelectrical-transduction channel of the hair cell is permeable to both monovalent and divalent cations. Hair cells are epithelial receptors that mediate mechanoelectrical transduction in the sensory organs of the vertebrate internal ear and lateral-line system (reviewed in ref.

Cited by 81 publications

References 40 publications

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Low Endolymph Calcium Concentrations in deafwaddler2J Mice Suggest that PMCA2 Contributes to Endolymph Calcium Maintenance

Steady-State Adaptation of Mechanotransduction Modulates the Resting Potential of Auditory Hair Cells, Providing an Assay for Endolymph [Ca²⁺]

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The selectivity of the hair cell’s mechanoelectrical-transduction channel promotes Ca 2+ flux at low Ca 2+ concentrations

Abstract: The mechanoelectrical-transduction channel of the hair cell is permeable to both monovalent and divalent cations. Hair cells are epithelial receptors that mediate mechanoelectrical transduction in the sensory organs of the vertebrate internal ear and lateral-line system (reviewed in ref.

Cited by 81 publications

References 40 publications

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Low Endolymph Calcium Concentrations in deafwaddler2J Mice Suggest that PMCA2 Contributes to Endolymph Calcium Maintenance

Steady-State Adaptation of Mechanotransduction Modulates the Resting Potential of Auditory Hair Cells, Providing an Assay for Endolymph [Ca2+]

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The selectivity of the hair cell’s mechanoelectrical-transduction channel promotes Ca ²⁺ flux at low Ca ²⁺ concentrations

Steady-State Adaptation of Mechanotransduction Modulates the Resting Potential of Auditory Hair Cells, Providing an Assay for Endolymph [Ca²⁺]