PIP₂-TMIE Interactions Drive Mammalian Hair Cell Slow Adaptation Independently of Myosin Motors

Sensory hair cells detect sound and balance through their apically located stereocilia bundles, converting mechanical stimuli into electrical signals via mechano-electrical transduction (MET) channels. These channels at the lower end of extracellular tip links connecting adjacent stereocilia are gated by tension. A key regulatory process of MET is slow adaptation, thought to enhance the auditory system's dynamic range. Traditionally, this process has been attributed to myosin motor activity. Here, we challenge this prevailing model and provide evidence for an alternative mechanism in which phosphatidylinositol 4,5-bisphosphate (PIP₂) modulates slow adaptation via interactions with the MET complex protein TMIE. Remarkably, adaptation was rescued by exogenous PIP₂ even when myosin motors were inhibited, highlighting PIP₂'s central role. Disruption of TMIE, a PIP₂-binding protein, also impaired adaptation, and we implicate a PIP₂ binding site between the channel candidate TMC1 and TMIE to mediate slow adaptation. These findings support a revised model in which PIP₂-TMIE/TMC1 interactions mediate slow adaptation in hair cells.