Thursday, November 21, 2024
11/21/2024
Project Summary Hair cells are auditory mechanoreceptors that use an apically located hair bundle to convert mechanical vibrations due to sound into electrical activity, a process termed mechanotransduction. The mechanotransduction process is essential to cochlear amplification, which is responsible for our excellent sound level sensitivity, large dynamic range, and amazing frequency discrimination. Loss of mechanotransduction leads to loss of cochlear amplification. Control of the range of sensitivity of the mechanotransduction process is hypothesized to be a key contributor to augmenting the dynamic range. In this proposal, we will investigate two mechanisms that can control the range of stimuli to which the hair cell is responsive. Mechanotransduction adaptation can adjust the range of sensitivity in the presence of an ongoing stimulus. One type of adaptation described decades ago is termed slow adaptation due to its kinetics. Slow adaptation was hypothesized to function via the motor model of adaptation. We recently overturned the motor model of slow adaptation, and we now propose a new model of slow adaptation requiring the phosphoinositide PIP2. In this proposal, we build upon our existing data by studying specific mutations in TMC1, the putative mechanotransduction channel, that we hypothesize to have a role in mediating PIP2 binding to modulate channel function. These experiments will provide mechanistic insight for slow adaptation. The second mechanism of sensitivity control is through cAMP. We recently discovered that cAMP functions to reduce gating spring stiffness, thereby controlling the sensitivity of the mechanotransduction channel. In this proposal, we will study the upstream and downstream signaling pathways using knockout mouse models to identify the molecular contributors to the pathway. These models will allow us to also identify the physiological role of the cAMP pathway in the cochlea. These experiments will lead us one step closer to understanding the role of cAMP in normal hearing function and identifying the molecular component(s) of the gating spring, which is the final downstream target.
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