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. 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. We recently showed a Ca2+ independent form of adaptation (Peng et. al, 2013), which indicated that we understood less about the mechanisms of adaptation in the mammalian auditory system than previously thought. We now have the opportunity to define the mechanisms of adaptation, so that we are able to better understand the mechanotransduction process.

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Figure 1. Adaptation shifts the mechantransduction activation curve. (Left) Stimulus protocol (upper traces) eliciting an adaptive shift in the mechanotransduction sensitivity curve. (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 warrranted. 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. Additionally, Myosin Ic was posited as the slow adaptation motor, however, our work suggests limited motor contribution to adaptation in the mammalian auditory system. Thus further investigations of the function of this myosin motor in cochlear hair cells is also warranted.

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Figure 2. (Left) Myosin motors are thought to reside at the upper ends of tip-links. (Right) Model of function of various mechanotransduction mechanisms.

Lipid Membrane

We have recently identified modulation of mechanotransduction properties 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 in order to determine the contribution of the lipid membrane to the mechanotransduction process.

Methods

We develop tools to push the limits of technology in order to directly answer questions related to auditory mechanotransduction. See a few features of our techniques below.