Abstract
The ability of cochlear hair cells to convert sound into receptor potentials relies on the mechanoelectrical transducer (MET) channels present in their stereociliary bundles. There is strong evidence implying that transmembrane channel-like protein (TMC) 1 contributes to the pore-forming subunit of the mature MET channel, yet its expression is delayed (~>P5 in apical outer hair cells, OHCs) compared to the onset of mechanotransduction (~P1). Instead, the temporal expression of TMC2 coincides with this onset, indicating that it could be part of the immature MET channel. We investigated MET channel properties from OHCs of homo- and heterozygous Tmc2 knockout mice. In the presence of TMC2, the MET channel blocker dihydrostreptomycin (DHS) had a lower affinity for the channel, when the aminoglycoside was applied extracellularly or intracellularly, with the latter effect being more pronounced. In Tmc2 knockout mice OHCs were protected from aminoglycoside ototoxicity during the first postnatal week, most likely due to their small MET current and the lower saturation level for aminoglycoside entry into the individual MET channels. DHS entry through the MET channels of Tmc2 knockout OHCs was lower during the first than in the second postnatal week, suggestive of a developmental change in the channel pore properties independent of TMC2. However, the ability of TMC2 to modify the MET channel properties strongly suggests it contributes to the pore-forming subunit of the neonatal channel. Nevertheless, we found that TMC2, different from TMC1, is not necessary for OHC development. While TMC2 is required for mechanotransduction in mature vestibular hair cells, its expression in the immature cochlea may be an evolutionary remnant.
Highlights
The conversion of acoustic mechanical stimuli into electrical signals, known as mechanoelectrical transduction (MET), is essential for our sense of hearing and is performed by the stereociliary bundle, a staircase-like structure of actin–based protrusions found at the apex of cochlear hair cells
We have performed a set of experiments to provide more insights into the biophysical and developmental contribution of TMC2 to mechano-electrical transduction in cochlear outer hair cells (OHCs)
As previously reported (Kim and Fettiplace, 2013), the maximum amplitude of the MET current was significantly reduced (P < 0.0001) in apical OHCs of Tmc2−/− compared to Tmc2+/− mice at P4 and postnatal day 5 (P5)
Summary
The conversion of acoustic mechanical stimuli into electrical signals, known as mechanoelectrical transduction (MET), is essential for our sense of hearing and is performed by the stereociliary bundle, a staircase-like structure of actin–based protrusions found at the apex of cochlear hair cells. The full molecular identity of the MET channel is still unknown; it is possible that the MET channel is not one molecule but a complex that can vary in composition with age and along the tonotopic axis of the cochlea (Kawashima et al, 2011; Zhao et al, 2014). Recent evidence has shown that Piezo 1 and Piezo 2, which constitute the pore forming subunit of other mechanosensitive channels (Coste et al, 2010, 2012; Woo et al, 2014), do not contribute to the MET channel complex located at the tip of the outer hair cell (OHC) stereociliary bundles (Corns and Marcotti, 2016; Wu et al, 2017). Changes in Ca2+ permeability and DHS affinity of the anomalous MET channel have been investigated in hair cells lacking both TMC1 and TMC2 (knockout mice: Kim et al, 2013; Beurg et al, 2014)
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