We have an exquisite sense of hearing, where we are able to encode over 12 orders of magnitude in intensity and discriminate between two tones that differ in only 0.2% in frequency. These abilities originate from the auditory periphery’s ability to detect sound. A key process in the detection lies in the mechano-electrical transduction (mechanotransduction) process that happens in the stereocilia hair bundle (highlighted in middle image above). Failures of this process lead to multiple causes of genetic deafness and likely underlie some forms of noise induced and age related hearing loss. In our lab, we are interested in the molecular mechanisms of the mammalian auditory mechanotransduction process. We use state-of-the-art technology to elucidate these mechanisms.

Adaptation

A key mechanism surrounding mechanotransduction is adaptation. Adaptation is posited to contribute to the amazing dynamic range of the auditory system, control the set point of the system, as well as contribute to mechanical filtering of incoming signals. Adaptation can be divided into at least two forms, which are named based on the kinetics (fast and slow). We previously showed fast adaptation does not require Ca2+ (Peng et al., 2013), which indicated that we understood less about the mechanisms of adaptation in the mammalian auditory system than previously thought. More recently, when studying the slow adaptation mechanism, we discovered that the prevailing model of slow adaptation (motor model) is no longer supported (Caprara et al., 2020). We now have the opportunity to define the mechanisms of adaptation, so that we are able to better understand the mechanotransduction process.

Figure 1. Adaptation is a decline in current due to a sustained stimulus and shifts the mechantransduction activation curve. (Left) Stimulus protocol (upper traces) eliciting an adaptive shift in the mechanotransduction sensitivity curve and showing the current decline indicative of adaptation. (Right) Activation curves showing the shift in the curve due to an adapting step.

 

Myosin Motors

Myosin motors are important to mechanotransduction, but their specific contributions to the process remain debated. Mouse models of Myosin VIIa, Myosin Ic, and Myosin XVa deficiencies have been shown to have a functional change in mechanotransduction properties. However, in light of recent data, revisiting these motors is warranted. Recent work (Marcotti et al., 2014) has overturned the interpretation of data regarding the function of Myosin VIIa in hair cells (Kros et al., 2002), leaving the true function of myosin VIIa in hair cells to be determined. In collaboration with Jung-Bum Shin's lab at the University of Virginia, we recently provided the first functional evidence that myosin VIIa generates the resting tension in the tip-link which is required for the high sensitivity of the auditory system (Li et al., 2020). This work also identified multiple isoforms of myosin VIIa and their specific roles in mechanotransduction are currently being explored.

 

Myosin Ic was posited as the slow adaptation motor in the motor model, however, mechanotransduction channel localization and developmental expression profiles of myosin Ic suggest the contrary in cochlear hair cells. In our recent work, we challenged the motor model of slow adaptation and determined that myosin Ic is important for slow adaptation in vestibular hair cells, but not in cochlear hair cells (Caprara et al., 2020). What myosin motor is important for cochlear slow adaptation? What is myosin Ic's role in slow adaptation if the motor model is incorrect? What is the role of myosin Ic in cochlear hair cells? These questions are the subject of ongoing investigations.

Figure 2. (A) Motor model of slow adaptation posited that myosin motors located at the upper-tip-link insertion were responsible for both slow adaptation and generating the resting tension in the tip link that is necessary for the sensitivity of the auditory system. (B) in our revised model, we hypothesize that different myosin motors are responsible for each function. Myosin motors at the upper-tip-link insertion are necessary for resting tip-link tension, and we hypothesize these motors are myosin VIIa. Slow adaptation myosin motors are likely functioning closer to the mechanotransduction channels and potentially require PIP2.

Lipid Membrane

We have identified modulation of mechanotransduction properties using the tarantula toxin GsMTx4 that likely occurs through the lipid bilayer (figure 2; Peng et al., 2016). This new mode of modulation requires a specific mechanism. We will use existing tools and develop new tools in order to manipulate the lipid composition in hair cell stereocilia to determine the contribution of the lipid membrane to the mechanotransduction process.