Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells

Indzhykulian, Artur A.; Stepanyan, Ruben; Nelina, Anastasiia; Spinelli, Kateri J.; Ahmed, Zubair M.; Belyantseva, Inna A.; Friedman, Thomas B.; Barr-Gillespie, Peter G.; Frolenkov, Gregory I.

doi:10.1371/journal.pbio.1001583

Cited by 121 publications

(172 citation statements)

References 53 publications

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“…The fluid jet was preferred to a rigid probe (17,19) because it does not require any direct contact with the stereocilia, which could affect their resting position and also damage some of the interciliary links (16). Unless the shape of the probe is perfectly matched to that of the V-or U-shaped bundle of the OHCs or IHCs, respectively, this method would also lead to nonuniform displacement of individual stereocilia (16,25,26). Such uniformity is achieved with fluid jet stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The disadvantage of the rigid probe, compared with the fluid jet, is that it requires optimal vertical and angular positioning to produce a homogeneous displacement of the V-or Ushaped hair bundle of OHCs and IHCs, respectively. Because the glass probe may not contact some stereocilia, when the probe is displaced (16,25), all stereociliary rows are initially deflected by viscous coupling, but then those not in direct contact with the probe relax, producing an artifactual adaptation (see also Materials and Methods). Indeed, it has been demonstrated that when the vertical positioning of the rigid probe was not optimal in respect to the bundle of cochlear OHCs, it produced an artifactually large and Ca 2+ -independent MET current decay (25), similar to that observed in ref.…”

Section: Discussionmentioning

confidence: 99%

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Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Corns

Johnson

Kros

et al. 2014

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

109

186

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Mechanotransduction in the auditory and vestibular systems depends on mechanosensitive ion channels in the stereociliary bundles that project from the apical surface of the sensory hair cells. In lower vertebrates, when the mechanoelectrical transducer (MET) channels are opened by movement of the bundle in the excitatory direction, Ca 2+ entry through the open MET channels causes adaptation, rapidly reducing their open probability and resetting their operating range. It remains uncertain whether such Ca 2+ -dependent adaptation is also present in mammalian hair cells. Hair bundles of both outer and inner hair cells from mice were deflected by using sinewave or step mechanical stimuli applied using a piezo-driven fluid jet. We found that when cochlear hair cells were depolarized near the Ca 2+ reversal potential or their hair bundles were exposed to the in vivo endolymphatic Ca 2+ concentration (40 μM), all manifestations of adaptation, including the rapid decline of the MET current and the reduction of the available resting MET current, were abolished. MET channel adaptation was also reduced or removed when the intracellular Ca 2+ buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) was increased from a concentration of 0.1 to 10 mM. The findings show that MET current adaptation in mouse auditory hair cells is modulated similarly by extracellular Ca 2+ , intracellular Ca 2+ buffering, and membrane potential, by their common effect on intracellular free Ca 2+ .H earing and balance depend on the transduction of mechanical stimuli into electrical signals. This process depends on the opening of mechanoelectrical transducer (MET) channels located at the tips of the shorter of pairs of adjacent stereocilia (1), which are specialized microvilli-like structures that form the hair bundles that project from the upper surface of hair cells (2,3). Deflection of hair bundles in the excitatory direction (i.e., toward the taller stereocilia) stretches specialized linkages, the tip-links, present between adjacent stereocilia (3-5), opening the MET channels. In hair cells from lower vertebrates, open MET channels reclose during constant stimuli via an initial fast adaptation mechanism followed by a much slower, myosin-based motor process, both of which are driven by Ca 2+ entry through the channel itself (6-13). In mammalian auditory hair cells, MET current adaptation seems to be mainly driven by the fast mechanism (14-16), although the exact process by which it occurs is still largely unknown. The submillisecond speed associated with the adaptation kinetics of the MET channels in rat and mouse cochlear hair cells (17,18) indicates that Ca 2+ , to cause adaptation, has to interact directly with a binding site on the channel or via an accessory protein (16). However, a recent investigation on rat auditory hair cells has challenged the view that Ca 2+ entry is required for fast adaptation, and instead proposed an as-yetundefined mechanism involving a Ca 2+ -independent reduction in the viscoelastic force of ele...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Corns

Johnson

Kros

et al. 2014

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

109

186

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“…Crystallographic structural evaluation revealed that the first and second ectodomains of cadherin 23 and protocadherin 15 interact with each other in a "handshake" mode to form the tip-link filaments (31). The current hypothesis is that the mature tip links are formed by protocadherin 15 and cadherin 23 (21), although during regeneration the transient but functional tip links are made of two protocadherin 15 isoforms (18). USH proteins myosin VIIa, harmonin, and sans are also found at the upper attachment of the tip link (9,12,15).…”

mentioning

confidence: 97%

Usher proteins in inner ear structure and function

Ahmed

Frolenkov

Riazuddin

2013

Physiological Genomics

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“…Two closely related pcdh15 genes have been identified in zebrafish (Seiler et al, 2005), with Pcdh15a involved in hearing and vestibular functions presumably through the formation of the tip links that gate the mechanotransduction channels, as is the case in mammalian hair cells (Kazmierczak et al, 2007;Indzhykulian et al, 2013). We generated Pcdh15a MOs and tested them for dye uptake impairment.…”

Section: Characterization Of Clarin-1 Mosmentioning

confidence: 99%

Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly

Ogun¹,

Zallocchi²

2014

J Gen Physiol

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Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells

Abstract: Backscatter scanning electron microscopy and conventional whole cell patch-clamp experiments reveal a two-step mechanism for the regeneration of tip links, the crucial element of mechanotransduction machinery in the hair cells of the inner ear.

Cited by 121 publications

References 53 publications

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Usher proteins in inner ear structure and function

Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly

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