Fast adaptation and Ca ²⁺ sensitivity of the mechanotransducer require myosin-XVa in inner but not outer cochlear hair cells

In inner ear hair cells, activation of mechanotransduction channels is followed by extremely rapid deactivation that depends on the influx of Ca ²⁺ through these channels. Although the molecular mechanisms of this "fast" adaptation are largely unknown, the predominant models assume Ca ²⁺ sensitivity as an intrinsic property of yet unidentified mechanotransduction channels. Here, we examined mechanotransduction in the hair cells of young postnatal shaker 2 mice (Myol5 ^sh2/sh2). These mice have no functional myosin-XVa, which is critical for normal growth of mechanosensory stereocilia of hair cells. Although stereocilia of both inner and outer hair cells of Myol5 ^sh2/sh2 mice lack myosin-XVa and are abnormally short, these cells have dramatically different hair bundle morphology. MyolS ^sh2/sh2 Outer hair cells retain a staircase arrangement of the abnormally short stereocilia and prominent tip links. Myol5 ^sh2/sh2inner hair cells do not have obliquely oriented tip links, and their mechanosensitivity is mediated exclusively by "top-to-top" links between equally short stereocilia. In both inner and outer hair cells of Myol5 ^sh2/sh2 mice, we found mechanotransduction responses with a normal "wild-type" amplitude and speed of activation. Surprisingly, only outer hair cells exhibit fast adaptation and sensitivity to extracellular Ca. In Myol5 ^sh2/sh2 inner hair cells, fast adaptation is disrupted and the transduction current is insensitive to extracellular Ca ²⁺. We conclude that the Ca ²⁺ sensitivity of the mechanotransduction channels and the fast adaptation require a structural environment that is dependent on myosin-XVa and is disrupted in Myol5 ^sh2/sh2 inner hair cells, but not in Myol5 ^sh2/sh2 outer hair cells.