The elegant biophysical analyses of hair cell mechanotransduction have led to a widely accepted hypothesis of the steps involved in converting hair bundle deflection into a receptor potential. At the core of this process is a multi-protein complex located near the tips of the stereocilia that consists of one or more mechanically gated cation channels, closely associated elastic structures and a tip link, a connector between the tip of one stereocilium with the side of the next tallest stereocilium. Mechanical deflection of the hair cell's stereocilia bundle in the positive direction is hypothesized to increase the tension in the tip link and in an elastic element that is part of the transduction machinery. This increased mechanical tension probably leads to a deformation of the transduction channel protein, which in turn, increases the open probability of the ion channel's gate. In invertebrates, a similar mechanism has been proposed to take place in chordotonal mechanosensory neurons and the tactile bristle mechanosensors. Three TRP cation channels have been implicated in Drosophila melanogaster mechanosensory transduction: Nanchung and Inactive, as well as NompC, whose vertebrate orthologue TRPN1 has been shown to be essential for hair cell function in zebrafish larvae. This grant application proposes to solve the atomic structure of mechanosensory transduction channel candidates. The planned approach will focus on TRP cation channels, specifically on zebrafish TRPN1, fruit fly Nanchung and Inactive, and the mammalian candidates TRPV4, TRPML3 (MCOLN3), TRPA1, and PKD1L3, which are all expressed by hair cells. Mechanotransduction is the underlying principle of hearing and balance. An important step toward fully understanding how the inner ear works requires knowledge about the detailed structure of the hair cell's transduction apparatus. The research described in this grant will lay the groundwork for gathering this knowledge. Basic research on the molecular basis of hearing and balance has tremendous impact on developing novel treatment for inner ear diseases because the crucial details that we hope to gather could be of importance for example for the development of novel sound amplification devices or future therapies aimed at replacing or repairing hair cells of the vestibular or auditory apparatus. ? ? ?
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