Caprara, G. A.; Kim, Y.; Jun, S.; Li, S.; Kim, U.; Shin, J.-B.; Peng, A. W.

Hair cells and their apically located stereocilia bundle are responsible for detecting sound and balance, by converting mechanical stimuli into electrical signals through the mechano-electric transduction (MET) channels, located at the lower end of the tip link connecting adjacent stereocilia. A long-studied regulation of the MET process is slow adaptation, which is hypothesized to contribute to the auditory systems remarkable dynamic range. Recent studies challenged the old model of slow adaptation which centered around myosin motors. We support a new model of slow adaptation that relies on phosphatidylinositol 4,5-bisphosphate (PIP2) interactions with the MET complex protein Tmie. First, we further support the hypothesized location of the slow adaptation mechanism at the lower end of the tip link by showing that slow adaptation is independent of myosin VIIa, located at the upper end of the tip link. Next, in both cochlear and vestibular hair cells, we demonstrate the reliance of slow adaptation on PIP2. Most strikingly, slow adaptation was rescued with exogenous PIP2 when myosin motors were inhibited, indicating the primary importance of PIP2. Finally, we suggest the importance of Tmie that binds PIP2 in the slow adaptation mechanism. These data support a new model of slow adaptation where PIP2 interactions with Tmie mediate slow adaptation in mammalian hair cells with myosin motors having a classic cargo transport role.