Generation of somatic electromechanical force by outer hair cells may be influenced by prestin–CASK interaction at the basal junction with the Deiter’s cell

Cimerman, Jelka; Waldhaus, Jörg; Harasztosi, Csaba; Duncker, Susanne V.; Dettling, Juliane; Heidrych, Paulina; Bress, Andreas; Gampe-Braig, Claudia; Frank, Gerhard; Gummer, Anthony W.; Oliver, Dominik; Knipper, Marlies; Zimmermann, Ulrike

doi:10.1007/s00418-013-1085-x

Cited by 13 publications

(8 citation statements)

References 59 publications

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“…Expression levels and voltage‐dependent characteristics of prestin can be assessed by electrophysiological recordings of charge movement or—equivalently—nonlinear capacitance (NLC), both resulting from prestin's voltage sensor . Since NLC amplitude and voltage dependence systematically change with postnatal development , NLC can also be used as a measure of OHC functional maturation . Normally, prestin expression reaches a mature level around p15 .…”

Section: Methodsmentioning

confidence: 99%

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

et al. 2017

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Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model.

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Section: Methodsmentioning

confidence: 99%

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

et al. 2017

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“…In response to a change in its transmembrane potential (Brownell et al ., ; Ashmore, ; Dallos & Evans, ) the OHC produces electromechanical force (Frank et al ., ) to amplify the vibration response of the cochlea. The molecular basis of this electromechanical transducer is the motor protein prestin (Zheng et al ., ), located in the OHC basolateral plasma membrane (Kalinec et al ., ; Huang & Santos‐Sacchi, ; Cimerman et al ., ). Prestin is essential for cochlear amplification and, therefore, normal hearing (Liberman et al ., ; Dallos, ).…”

Section: Introductionmentioning

confidence: 97%

The chloride‐channel blocker 9‐anthracenecarboxylic acid reduces the nonlinear capacitance of prestin‐associated charge movement

Harasztosi

Gummer

2016

Eur J Neurosci

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The basis of the extraordinary sensitivity and frequency selectivity of the cochlea is a chloride-sensitive protein called prestin which can produce an electromechanical response and which resides in the basolateral plasma membrane of outer hair cells (OHCs). The compound 9-anthracenecarboxylic acid (9-AC), an inhibitor of chloride channels, has been found to reduce the electromechanical response of the cochlea and the OHC mechanical impedance. To elucidate these 9-AC effects, the functional electromechanical status of prestin was assayed by measuring the nonlinear capacitance of OHCs from the guinea-pig cochlea and of prestin-transfected human embryonic kidney 293 (HEK 293) cells. Extracellular application of 9-AC caused reversible, dosedependent and chloride-sensitive reduction in OHC nonlinear charge transfer, Q max . Prestin-transfected cells also showed reversible reduction in Q max . For OHCs, intracellular 9-AC application as well as reduced intracellular pH had no detectable effect on the reduction in Q max by extracellularly applied 9-AC. In the prestin-transfected cells, cytosolic application of 9-AC approximately halved the blocking efficacy of extracellularly applied 9-AC. OHC inside-out patches presented the whole-cell blocking characteristics. Disruption of the cytoskeleton by preventing actin polymerization with latrunculin A or by decoupling of spectrin from actin with diamide did not affect the 9-AC-evoked reduction in Q max . We conclude that 9-AC acts on the electromechanical transducer principally by interaction with prestin rather than acting via the cytoskeleton, chloride channels or pH. The 9-AC block presents characteristics in common with salicylate, but is almost an order of magnitude faster. 9-AC provides a new tool for elucidating the molecular dynamics of prestin function.

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“…Yamashita and colleagues also reported that proteins in the OHC’s LM, including prestin, are virtually immobile ( Yamashita et al, 2015 ), suggesting that the prestin-embedded LM forms a distinct domain, separate from apical and basal membrane compartments. This unique arrangement of membrane domains appears to be functionally important, as hypothyroid animals, where prestin expression is observed along the entire basolateral membrane, have impaired hearing and reduced electromechanical force generation ( Cimerman et al, 2013 ). In this regard, prestin is the key intrinsic factor that separates motile OHCs from non-motile inner hair cells (IHC), which only have two (apical and basolateral) membrane compartments.…”

Section: Introductionmentioning

confidence: 99%

Prestin Contributes to Membrane Compartmentalization and Is Required for Normal Innervation of Outer Hair Cells

Takahashi

Sun

Zhou

et al. 2018

Front. Cell. Neurosci.

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Outer hair cells (OHC) act as amplifiers and their function is modified by medial olivocochlear (MOC) efferents. The unique OHC motor protein, prestin, provides the molecular basis for somatic electromotility, which is required for sensitivity and frequency selectivity, the hallmarks of mammalian hearing. Prestin proteins are the major component of the lateral membrane of mature OHCs, which separates apical and basal domains. To investigate the contribution of prestin to this unique arrangement, we compared the distribution of membrane proteins in OHCs of wildtype (WT) and prestin-knockout (KO) mice. In WT, the apical protein PMCA2 was exclusively localized to the hair bundles, while it was also found at the lateral membrane in KOs. Similarly, a basal protein KCNQ4 did not coalesce at the base of OHCs but was widely dispersed in mice lacking prestin. Since the expression levels of PMCA2 and KCNQ4 remained unchanged in KOs, the data indicate that prestin is required for the normal distribution of apical and basal membrane proteins in OHCs. Since OHC synapses predominate in the basal subnuclear region, we also examined the synaptic architecture in prestin-KO mice. Although neurite densities were not affected, MOC efferent terminals in prestin-KO mice were no longer constrained to the basal pole as in WT. This trend was evident as early as at postnatal day 12. Furthermore, terminals were often enlarged and frequently appeared as singlets when compared to the multiple clusters of individual terminals in WT. This abnormality in MOC synaptic morphology in prestin-KO mice is similar to defects in mice lacking MOC pathway proteins such as α9/α10 nicotinic acetylcholine receptors and BK channels, indicating a role for prestin in the proper establishment of MOC synapses. To investigate the contribution of prestin’s electromotility, we also examined OHCs from a mouse model that expresses non-functional prestin (499-prestin). We found no changes in PMCA2 localization and MOC synaptic morphology in OHCs from 499-prestin mice. Taken together, these results indicate that prestin, independent of its motile function, plays an important structural role in membrane compartmentalization, which is required for the formation of normal efferent-OHC synapses in mature OHCs.

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Generation of somatic electromechanical force by outer hair cells may be influenced by prestin–CASK interaction at the basal junction with the Deiter’s cell

Cited by 13 publications

References 59 publications

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

The chloride‐channel blocker 9‐anthracenecarboxylic acid reduces the nonlinear capacitance of prestin‐associated charge movement

Prestin Contributes to Membrane Compartmentalization and Is Required for Normal Innervation of Outer Hair Cells

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