Mechanotransduction and Adaptation in Mammalian Vestibular and Auditory Hair Cells

Stauffer, Eric Alan, Department of Neuroscience, University of Virginia
Holt, Jeffrey, Department of Neuroscience, University of Virginia
Brunjes, Peter, Department of Psychology, University of Virginia
Todorovic, Slobodan, Department of Anesthesiology, University of Virginia
Bloom, George, Department of Biology, University of Virginia
Friesen, Otto, Department of Biology, University of Virginia

The hair cell, the primary sensory receptor cell of the inner ear, transduces mechanical movements from auditory and vestibular stimuli into electrical signals which are then transmitted to the brain. Hair cells adapt to sustained stimuli by adjusting transduction channel open probability towards the resting value. A slow adaptation process involving a molecular motor serves to maximize stimulus sensitivity over a broad operating range, while a fast adaptation process may play an integral role in frequency tuning and amplification. There are two models for fast adaptation: a channel re-closure model and an alternative release model. By separating the fast and slow components of adaptation using the inferred shift method, I determined that fast adaptation in vestibular hair cells was fit best by the release model. I next wanted to find the molecular basis for fast adaptation. To determine if myosin-1c mediates fast adaptation in these cells, knock-in mice expressing the Y61G form of myosin-1c were created. The Y61G mutation renders myosin-1c sensitive to the allele-specific inhibitor NMB-ADP. I examined transduction and adaptation in the presence of NMB-ADP, and surprisingly found that inhibiting myosin1c not only blocked slow adaptation, but inhibited fast adaptation as well. Myosion-1c activity is required for fast adaptation, and may act as the release element driving fast adaptation in vestibular cells. The transduction and adaptation properties of mouse inner and outer auditory hair cells were next systematically characterized. Inner hair cells had a mean 10-90% 4 operating range of 0.86 µm, whereas outer hair cells had an operating range of 0.44 µm. Step deflections of auditory hair cell bundles using a stimulator with a fast rise time (~20 µs) evoked adaptation that had two components. Slow adaptation in auditory hair cells accounted for ~ 400f total adaptation, and the rate of slow adaptation was similar to its rate in vestibular hair cells. Fast adaptation properties were consistent with the release model. Inhibiting Myosin-1c with NMB-ADP did not significantly affect slow or fast adaptation in apical auditory outer hair cells, suggesting that Myosin-1c may have different functions in vestibular and auditory hair cells.

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PHD (Doctor of Philosophy)
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