Abstract
Hearing sensation relies on the mechano-electrical transducer (MET) channel of cochlear hair cells, in which transmembrane channel-like 1 (TMC1) and transmembrane channel-like 2 (TMC2) have been proposed to be the pore-forming subunits in mammals. TMCs were also found to regulate biological processes other than MET in invertebrates, ranging from sensations to motor function. However, whether TMCs have a non-MET role remains elusive in mammals. Here, we report that in mouse hair cells, TMC1, but not TMC2, provides a background leak conductance, with properties distinct from those of the MET channels. By cysteine substitutions in TMC1, we characterized four amino acids that are required for the leak conductance. The leak conductance is graded in a frequency-dependent manner along the length of the cochlea and is indispensable for action potential firing. Taken together, our results show that TMC1 confers a background leak conductance in cochlear hair cells, which may be critical for the acquisition of sound-frequency and -intensity.
Highlights
Hair cells are mechanoreceptors that convert mechanical stimuli provided by sound and acceleration into electrical signals
The amplitude of the background current (IBG) was calculated by subtracting the Im in 144 NMDG solution (INMDG) from that in 144 mM Na+-containing external solution (144 Na) solution (INa) (Figure 1B)
After subtraction, it was clear that the IBG altered almost linearly with holding potentials and was dramatically reduced in Tmc1-knockout outer hair cells (OHCs) (Figure 1I)
Summary
Hair cells are mechanoreceptors that convert mechanical stimuli provided by sound and acceleration into electrical signals. TMC1 and TMC2 have been proposed to be the pore-forming subunits of the MET channel in hair cells (Ballesteros et al, 2018; Corey and Holt, 2016; Kawashima et al, 2015; Pan et al, 2018) Consistent with this model, MET currents are absent in hair cells from mice lacking both TMC1 and TMC2 (Kawashima et al, 2011), while the unitary conductance, permeability, and ion selectivity of the. While efforts have failed to demonstrate that TMCs in flies and worms are mechanically gated ion channels, recent mechanistic studies in worms have shown that TMC1 and TMC2 regulate membrane excitability and egg-laying behavior by conferring a leak conductance (Yue et al, 2018) This raises the question of whether mammalian TMC1 and TMC2 only function as components of mechanically gated ion channels, or possess additional roles critical for mechanosensory hair-cell function. We sought out potential molecular and cellular mechanisms underlying TMCs and their correlated relevance in auditory transduction
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