<i>Tmc1</i>Point Mutation Affects Ca<sup>2+</sup>Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells

Corns, Laura F.; Johnson, Stuart L.; Kros, Corné J.; Marcotti, Walter

doi:10.1523/jneurosci.2439-15.2016

Cited by 65 publications

(96 citation statements)

References 51 publications

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“…This effect may be a significant factor contributing to the deafness phenotype. A similar behaviour was seen with the Tmc1 p.M412K (Beethoven) mutation (Beurg et al 2015;Corns et al 2016). A problem with respect to the underlying mechanism specifying P OR is that it may be modulated by other processes (Peng et al 2016).…”

Section: Discussionsupporting

confidence: 64%

“…; Corns et al . ). All measurements with the mutants were conducted using 1 m m BAPTA in the cytoplasmic solution.…”

Section: Resultsmentioning

confidence: 99%

“…5B). For comparison, values for the Tmc1 p.M412K mutation are also shown (Beurg et al 2015;Corns et al 2016). All measurements with the mutants were conducted using 1 mM BAPTA in the cytoplasmic solution.…”

Section: Resting Probability Of Met Channel Openingmentioning

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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Section: Discussionsupporting

confidence: 64%

“…; Corns et al . ). All measurements with the mutants were conducted using 1 m m BAPTA in the cytoplasmic solution.…”

Section: Resultsmentioning

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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“…In the presence of a functional Ca 2+ sensor, adaptation is not evident at low extracellular Ca 2+ (<0.1 m m ) or strong intracellular Ca 2+ buffering with BAPTA, but different from the findings with the sv / sv hair cells, this results in a large fraction of the MET current being activated at rest in wild‐type cochlear hair cells (Corns et al . , ) and +/ sv OHCs too (Figs and ). The combination of a lack of MET current decline during stimulation by mechanical steps and no resting MET current has been reported to occur at the onset of mechanosensitivity at P2–P3 for apical‐coil OHCs (Waguespack et al .…”

Section: Discussionmentioning

confidence: 76%

The acquisition of mechano‐electrical transducer current adaptation in auditory hair cells requires myosin VI

Marcotti

Corns

Goodyear

et al. 2016

The Journal of Physiology

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Key points The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano‐electrical transducer (MET) channels.The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli.In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles.We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop.We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role. AbstractMutations in Myo6, the gene encoding the (F‐actin) minus end‐directed unconventional myosin, myosin VI, cause hereditary deafness in mice (Snell's waltzer) and humans. In the sensory hair cells of the cochlea, myosin VI is expressed in the cell bodies and along the stereocilia that project from the cells’ apical surface. It is required for maintaining the structural integrity of the mechanosensitive hair bundles formed by the stereocilia. In this study we investigate whether myosin VI contributes to mechano‐electrical transduction. We report that Ca2+‐dependent adaptation of the mechano‐electrical transducer (MET) current, which serves to keep the transduction apparatus operating within its most sensitive range, is absent in outer and inner hair cells from homozygous Snell's waltzer mutant mice, which fail to express myosin VI. The operating range of the MET channels is also abnormal in the mutants, resulting in the absence of a resting MET current. We found that cadherin 23, a component of the hair bundle's transient lateral links, fails to be downregulated along the length of the stereocilia in maturing Myo6 mutant mice. MET currents of heterozygous littermates appear normal. We propose that myosin VI, by removing key molecules from developing hair bundles, is required for the development of the MET apparatus and its Ca2+‐dependent adaptation.

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“…A lack of TMC1 prior to P7 is compensated for by TMC2, but the latter isoform is down-regulated after P7. Third, Tmc1 mutations alter MET channel unitary conductance (145) (223) (23) and the Ca 2+ permeability of the channel (146) (223) (18) (49). Finally, during the first neonatal week, when TMC2 is also present in mouse cochlear hair cells, Tmc1 knockout virtually abolishes the tonotopic gradient in single MET-channel conductance.…”

Section: Hair Cell Transductionmentioning

confidence: 99%

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

Fettiplace

2017

Comprehensive Physiology

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273

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Sound pressure fluctuations striking the ear are conveyed to the cochlea, where they vibrate the basilar membrane on which sit hair cells, the mechanoreceptors of the inner ear. Recordings of hair cell electrical responses have shown that they transduce sound via sub-micrometer deflections of their hair bundles, which are arrays of interconnected stereocilia containing the mechanoelectrical transducer (MET) channels. MET channels are activated by tension in extracellular tip links bridging adjacent stereocilia, and they can respond within microseconds to nanometer displacements of the bundle, facilitated by multiple processes of Ca2+-dependent adaptation. Studies of mouse mutants have produced much detail about the molecular organization of the stereocilia, the tip links and their attachment sites, and the MET channels localized to the lower ends of each tip link. The mammalian cochlea contains two categories of hair cells. Inner hair cells relay acoustic information via multiple ribbon synapses that transmit rapidly without rundown. Outer hair cells are important for amplifying sound-evoked vibrations. The amplification mechanism primarily involves contractions of the outer hair cells, which are driven by changes in membrane potential and mediated by prestin, a motor protein in the outer hair cell lateral membrane. Different sound frequencies are separated along the cochlea, with each hair cell being tuned to a narrow frequency range; amplification sharpens the frequency resolution and augments sensitivity 100-fold around the cell’s characteristic frequency. Genetic mutations and environmental factors such as acoustic overstimulation cause hearing loss through irreversible damage to the hair cells or degeneration of inner hair cell synapses.

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Tmc1Point Mutation Affects Ca²⁺Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells

Cited by 65 publications

References 51 publications

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

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

The acquisition of mechano‐electrical transducer current adaptation in auditory hair cells requires myosin VI

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

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Tmc1Point Mutation Affects Ca2+Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells

Cited by 65 publications

References 51 publications

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

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

The acquisition of mechano‐electrical transducer current adaptation in auditory hair cells requires myosin VI

Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

Contact Info

Product

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Tmc1Point Mutation Affects Ca²⁺Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells