Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea

Beurg, Maryline; Cui, Runjia; Goldring, Adam C.; Ebrahim, Seham; Fettiplace, Robert; Kachar, Bechara

doi:10.1038/s41467-018-04589-8

Cited by 87 publications

(136 citation statements)

References 44 publications

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“…2 and 10). TMC1-mCherry in P7 IHCs (9) or P10 IHCs (20) in previous studies appeared more diffuse than TMC1-FLAG in P5 IHCs in our study (Fig. 2B), and it is unclear whether the diffuse distribution of TMC1-mCherry was due to the overexpression of 7 copies of the TMC1-mCherry transgene in the specific mouse line used or whether the observed difference is due to a disparity in detection sensitivity in these studies.…”

Section: Tmc1 Localization In Neonatal Hair Cellscontrasting

confidence: 61%

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

Chen

et al. 2019

FASEB j.

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The channel that governs mechanotransduction (MT) by hair cells in the inner ear has been investigated intensively for 4 decades, but its precise molecular composition remains enigmatic. Transmembrane channel‐like protein 1 (TMC1) was recently identified as a component of the MT channel, and lipoma HMGIC fusion partner‐like 5 (LHFPL5) is considered to be part of the MT complex and may functionally couple the tip link to the MT channel. As components of the MT complex, TMC1 and LHFPL5 are expected to localize at the lower end of the tip link in hair cells, a notion generally supported by previous studies on neonatal mice. However, the localization of these 2 proteins, particularly in the hair cells of adult mice, remains incompletely elucidated. Because determination of TMC1 and LHFPL5 localization at distinct developmental stages is essential for understanding their function and regulation, we used several approaches to examine the localization of these proteins in neonatal and adult hair cells in the mouse. We report several notable findings: 1) TMC1 and LHFPL5 predominantly localize at the tip of the shorter rows of stereocilia in neonatal hair cells, which largely verifies the previously published findings in neonatal hair cells; 2) LHFPL5 persists in the hair bundle of hair cells after postnatal day (P)7, which clarifies the previously reported unexpected absence of LHFPL5 after P7 and supports the view that LHFPL5 is a permanent component in the MT complex; and 3) TMC1 and LHFPL5 remain at the tip of the shorter rows of stereocilia in adult outer hair cells, but in adult inner hair cells, TMC1 is uniformly distributed in both the tallest row and the shorter rows of stereocilia, whereas LHFPL5 is uniformly distributed in the shorter rows of stereocilia. These findings raise intriguing questions regarding the turnover rate, regulation, additional functions, and functional interaction of TMC1 and LHFPL5. Our study confirms the previous findings in neonatal hair cells and reveals several previously unidentified aspects of TMC1 and LHFPL5 localization in more mature hair cells.—Li, X., Yu, X., Chen, X., Liu, Z., Wang, G., Li, C., Wong, E. Y. M., Sham, M. H., Tang, J., He, J., Xiong, W., Liu, Z., Huang, P. Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice. FASEB J. 33,6838–6851 (2019). http://www.fasebj.org

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Section: Tmc1 Localization In Neonatal Hair Cellscontrasting

confidence: 61%

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

Chen

et al. 2019

FASEB j.

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“…TMC2‐containing channels have a 17% smaller unitary conductance, 58 pS compared to 70 pS (Beurg et al . ), although this is offset by a 40% larger permeability to Ca 2+ ( P Ca / P Cs = 6.0 for TMC2 compared to 4.2 for TMC1 (Kim & Fettiplace, ) (Fig. G ).…”

Section: Resultsmentioning

confidence: 97%

“…Δ X/A was 0.29 ± 0.01 ( N = 4) in Tmc1 +/+ ;Tmc2 +/+ mice and Δ X/A was 0.40 ± 0.01 ( n = 5) in Tmc1 +/+ ;Tmc2 –/– mice; maximum MET currents were 0.97 ± 0.03 nA in Tmc1 +/+ ;Tmc2 +/+ and 0.55 ± 0.03 nA in Tmc1 +/+ ;Tmc2 –/– , both in P6 mice.The smaller current in Tmc2 –/– at this age reflects the fact that TMC2 contributes significantly to the IHC MET channels (Beurg et al . ).…”

Section: Resultsmentioning

confidence: 99%

“…; Beurg et al . ). Tmc1 –/– mice lack MET currents in OHCs after postnatal day (P)8 and are deaf (Kawashima et al .…”

Section: Introductionmentioning

confidence: 99%

“…The two TMC isoforms have been localized to the site of the MET channels at the tips of the shorter stereocilia (Kurima et al 2015) and a mutation in either isoform alters ion conduction through the MET channels Pan et al 2013;Beurg et al 2014). TMC2 is expressed early in mouse post-natal development but is replaced by TMC1 by the end of the first postnatal week (Kawashima et al 2011;Beurg et al 2018). Tmc1 -/mice lack MET currents in OHCs after postnatal day (P)8 and are deaf (Kawashima et al 2011;.…”

Section: Introductionmentioning

confidence: 99%

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The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

Goldring

Beurg

Fettiplace

2019

The Journal of Physiology

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Key points Hair cell mechanoelectrical transducer channels are opened by deflections of the hair bundle about a resting position set by incompletely understood adaptation mechanisms. We used three characteristics to define adaptation in hair cell mutants of transmembrane channel‐like proteins, TMC1 and TMC2, which are considered to be channel constituents. The results obtained demonstrate that the three characteristics are not equivalent, and raise doubts about simple models in which intracellular Ca2+ regulates adaptation. Adaptation is faster and more effective in TMC1‐containing than in TMC2‐containing transducer channels. This result ties adaptation to the channel complex, and suggests that TMC1 is a better isoform for use in cochlear hair cells. We describe a TMC1 point mutation, D569N, that reduces the resting open probability and Ca2+ permeability of the transducer channels, comprising properties that may contribute to the deafness phenotype. Abstract Recordings of mechanoelectrical transducer (MET) currents in cochlear hair cells were made in mice with mutations of transmembrane channel‐like (TMC) protein to examine the effects on fast transducer adaptation. Adaptation was faster and more complete in Tmc2–/– than in Tmc1–/–, although this disparity was not explained by differences in Ca2+ permeability or Ca2+ influx between the two isoforms, with TMC2 having the larger permeability. We made a mouse mutation, Tmc1 p.D569N, homologous to a human DFNA36 deafness mutation, which also had MET channels with lower Ca2+‐permeability but showed better fast adaptation than wild‐type Tmc1+/+ channels. Consistent with the more effective adaptation in Tmc1 p.D569N, the resting probability of MET channel opening was smaller. The three TMC variants studied have comparable single‐channel conductances, although the lack of correlation between channel Ca2+ permeability and adaptation opposes the hypothesis that adaptation is controlled simply by Ca2+ influx through the channels. During the first postnatal week of mouse development, the MET currents amplitude grew, and transducer adaptation became faster and more effective. We attribute changes in adaptation partly to a developmental switch from TMC2‐ to TMC1‐ containing channels and partly to an increase in channel expression. More complete and faster adaptation, coupled with larger MET currents, may account for the sole use of TMC1 in the adult cochlear hair cells.

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Cochlear tonotopy from proteins to perception

Fettiplace

2023

BioEssays

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A ubiquitous feature of the auditory organ in amniotes is the longitudinal mapping of neuronal characteristic frequencies (CFs), which increase exponentially with distance along the organ. The exponential tonotopic map reflects variation in hair cell properties according to cochlear location and is thought to stem from concentration gradients in diffusible morphogenic proteins during embryonic development. While in all amniotes the spatial gradient is initiated by sonic hedgehog (SHH), released from the notochord and floorplate, subsequent molecular pathways are not fully understood. In chickens, BMP7 is one such morphogen, secreted from the distal end of the cochlea. In mammals, the developmental mechanism differs from birds and may depend on cochlear location.A consequence of exponential maps is that each octave occupies an equal distance on the cochlea, a spacing preserved in the tonotopic maps in higher auditory brain regions. This may facilitate frequency analysis and recognition of acoustic sequences.

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Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea

Cited by 87 publications

References 44 publications

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells

Cochlear tonotopy from proteins to perception

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