Transduction without Tip Links in Cochlear Hair Cells Is Mediated by Ion Channels with Permeation Properties Distinct from Those of the Mechano-Electrical Transducer Channel

Marcotti, Walter; Corns, Laura F.; Desmonds, Terri; Kirkwood, Nerissa K.; Richardson, Guy P.; Kros, Corné J.

doi:10.1523/jneurosci.4086-13.2014

Cited by 46 publications

(94 citation statements)

References 39 publications

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“…Based on their properties (single-channel conductance, block by FM1-43 and Ca 2+ selectivity), the unconventional MT currents recorded during development in wild-type mice and those seen under abnormal conditions (in mutants or after tip-link destruction) are manifestations of the same ion channel. Reversepolarity MT currents were previously found to occur embryonically (12), but no subsequent pattern of development or relationship to the normal MT current was evident in that work, and it was further claimed that the reverse-polarity current persisted until at least P10, which we never saw. One hypothesis is that the unconventional channels are associated with the small microvilli that carpet the top surface of hair cells behind the hair bundle, and their transient neonatal appearances are linked.…”

Section: Discussioncontrasting

confidence: 59%

“…A difficulty with assigning significance to the reverse-polarity MT currents stems from them being recorded only under abnormal circumstances, whether by tip-link disruption or mutations that adversely affect mechanotransduction. Previous work had, however, suggested that this type of current may also be present constitutively during hair-cell development (10,12,14,18). More detailed investigation showed that hair cells first displayed mechanical sensitivity around birth, when it was manifested as a reverse-polarity current, always preceding the normal-polarity current ( Fig.…”

Section: Significancementioning

confidence: 89%

“…Nevertheless, it is unclear whether deleting both Tmc1 and Tmc2 completely abolishes mechanotransduction (7), or merely prevents the MT channels being targeted to the stereociliary tips, so they cannot be gated by tiplink tension (10). In Tmc1:Tmc2 double mutants, or after destruction of the tip links, the normal MT current is lost, only to be replaced by a mechanically sensitive current evoked by stimuli of reverse polarity (10)(11)(12). Whether the channels underlying these reverse-polarity currents are the same as those in unperturbed cells is uncertain (2,13).…”

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confidence: 99%

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Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells

Beurg

Goldring

Ricci

et al. 2016

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

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Cochlear hair cells normally detect positive deflections of their hair bundles, rotating toward their tallest edge, which opens mechanotransducer (MT) channels by increased tension in interciliary tip links. After tip-link destruction, the normal polarity of MT current is replaced by a mechanically sensitive current evoked by negative bundle deflections. The "reverse-polarity" current was investigated in cochlear hair cells after tip-link destruction with BAPTA, in transmembrane channel-like protein isoforms 1/2 (Tmc1:Tmc2) double mutants, and during perinatal development. This current is a natural adjunct of embryonic development, present in all wild-type hair cells but declining after birth with emergence of the normal-polarity current. Evidence indicated the reverse-polarity current seen developmentally was a manifestation of the same ion channel as that evident under abnormal conditions in Tmc mutants or after tip-link destruction. In all cases, sinusoidal fluid-jet stimuli from different orientations suggested the underlying channels were opened not directly by deflections of the hair bundle but by deformation of the apical plasma membrane. Cell-attached patch recording on the hair-cell apical membrane revealed, after BAPTA treatment or during perinatal development, 90-pS stretch-activated cation channels that could be blocked by Ca 2+ and by FM1-43. High-speed Ca 2+ imaging, using swept-field confocal microscopy, showed the Ca 2+ influx through the reverse-polarity channels was not localized to the hair bundle, but distributed across the apical plasma membrane. These reverse-polarity channels, which we propose to be renamed "unconventional" mechanically sensitive channels, have some properties similar to the normal MT channels, but the relationship between the two types is still not well defined.hair cells | mechanotransducer channels | calcium imaging | cochlea | transmembrane channel-like protein I on channels sensitive to mechanical deformation of the cell membrane are widely distributed in vertebrates and are integral to the function of specialized mechanoreceptors, such as those in the sensory neurons of the skin, vasculature, or inner ear. The molecular structure of these mechanically gated channels has been the subject of much recent research and speculation (1-4) because they are the last category of vertebrate ion-channel (after voltage-gated and ligand-activated channels) evading characterization. Although success was achieved by assigning piezo2 as a transduction channel in many cutaneous touch receptors (3), uncertainty persists about the composition of the mechanotransducer (MT) channel in hair cells of the inner ear (2, 4). There, the MT channels reside in the stereociliary (hair) bundle, where they are activated by deflections of the bundle toward the taller edge of the staircase, and so increasing tension in the oblique extracellular tip links connecting adjacent stereocilia. Transmembrane channel-like protein isoforms 1 and 2, TMC1 and TMC2 (5), have been suggested as candidates for the ha...

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Section: Discussioncontrasting

confidence: 59%

Section: Significancementioning

confidence: 89%

mentioning

confidence: 99%

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Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells

Beurg

Goldring

Ricci

et al. 2016

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

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“…Reverse-polarity currents also have been reported for TMC1/TMC2 double mutants (14) and other MT-disrupted hair cells (15), keeping open the nomination process for MT channel proteins. Knockout of LHFPL5 produced smaller single MT channel currents and flattened the tonotopic gradient in unitary conductance (for normal polarity motion, reverse-polarity currents appear similar in low-and high-frequency hair cells, although this was not quantified).…”

Section: Reverse-polarity Mechanotransductionmentioning

confidence: 61%

How many proteins does it take to gate hair cell mechanotransduction?

Fuchs

2015

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

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Components of the Mechanotransducer ComplexMechanosensory hair cells of the inner ear transduce sound or head motion into electrical signals through the gating of mechanically coupled ion channels. Although many cell types can respond to mechanical force (1), the disposition of mechanotransduction (MT) channels to the very tips of stereocilia (2, 3) confers onto hair cells of the inner ear their specialized sensitivity (4, 5). Differential deflection of the stereociliary tips is transmitted to the MT channels via extracellular "tiplinks" that extend between taller and shorter stereocilia (6-8). The tip-links are composed of cadherin 23 and protocadherin 15 (5), the latter of which forms the lower end coupled to the MT gating complex. Positional cloning of a human deafness locus identified transmembrane channel-like protein isoforms (TMC)1 and TMC2 as potential components of the MT complex (9). TMC1 and TMC2 interact with protocadherin 15 (10) and have been nominated as subunits of the channel itself (11), perhaps combining differentially to generate the tonotopic variation in unitary conductance (larger in higher frequency hair cells) (12). The challenge for the field is to establish molecular mechanisms in a cellular organelle (the hair bundle) that couples extracellular force to channel gating through a still incompletely defined complement of interacting proteins. The problem is compounded by the fact that the MT channel and its binding partners must be transported and assembled at the stereociliary tips. In PNAS, Beurg et al. (13) shine a revealing light onto these complexities. The authors show that LHFPL5 (lipoma HMGIC fusion partnerlike 5, also known as tetraspan membrane protein of hair cell stereocilia, or TMHS) is required for normal MT current, apparently by regulating the participation of TMC1 (but not TMC2). These results in themselves help to keep the story of haircell MT moving forward. However, the authors' description of "reverse-polarity" MT currents puts an intriguing twist into the plot. Reverse-Polarity MechanotransductionThe cornerstone of hair-cell MT is its directional specificity. Deflection toward the taller stereocilia causes MT channel opening, cationic influx, and hair-cell depolarization; the opposite motion causes channel closure (4). Incredibly, hair cells of homozygous LHFPL5 null (LHFPL5 −/− ) mice generate Beurg et al. propose that LHFPL5 is required for correct positioning of TMC1 in the MT complex, and in particular for the tonotopic gradient in unitary conductance of the MT channel.reverse-polarity MT currents that can be even larger than those for the normal polarity motion. Reverse-polarity currents also have been reported for TMC1/TMC2 double mutants (14) and other MT-disrupted hair cells (15), keeping open the nomination process for MT channel proteins. Knockout of LHFPL5 produced smaller single MT channel currents and flattened the tonotopic gradient in unitary conductance (for normal polarity motion, reverse-polarity currents appear similar in low-and high-frequency ha...

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“…The appearance of reversetransduction as a sign that functional bundle remodeling is under way is a tempting avenue to explore. Breaking the tip-link in the transduction complex clearly leads to reverse-transduction within about 5 min in immature hair cells (1,7,12), but it is not known whether the same occurs in adult hair cells. Beurg et al (1) suggest that it does not, at least to any significant extent.…”

mentioning

confidence: 99%

Stretching out the early steps in hearing

Ashmore¹

2016

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

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Transduction without Tip Links in Cochlear Hair Cells Is Mediated by Ion Channels with Permeation Properties Distinct from Those of the Mechano-Electrical Transducer Channel

Cited by 46 publications

References 39 publications

Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells

Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells

How many proteins does it take to gate hair cell mechanotransduction?

Stretching out the early steps in hearing

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