Transduction of the mechanical energy carried in sound and head movement into electrical signals is the critical responsibility of a hair cell, the key cell type of the auditory and vestibular systems. Although the transduction apparatus has largely resisted molecular characterization, due both to the paucity of hair cells and the seemingly unique mechanism of transduction, progress nevertheless has been made over the last decade. Exemplifying this progress is the demonstration that myosin-1c (formerly known as myosin-IB) is an adaptation-motor myosin in mouse utricular hair cells. Because hair-cell damage underlies many types of hearing disorders, and because damage to the transduction apparatus is a likely etiology for many examples of hearing loss, identification of the molecular components of the transduction apparatus should form the underpinning of rational approaches to alleviating hearing disorders. A combination of methods, including in vitro biochemistry, molecular cloning, hair-bundle isolation, morphological analysis, and mouse genetics, will be used to further characterize the molecular constituents of the transduction apparatus. Four projects will be pursued. (1) The regulation of myosin-1c will be examined in hair cells, determining how protein kinases and Ca2+ regulate the motor. (2) Exploiting the observation that the calmodulin-binding IQ domains of myosin-1c also bind unknown myosin-1c receptors in hair bundles, w biochemical purification and cDNA library screens ill be used to identify these receptors. (3) Using an anti-tip link antibody, the identity of the tip link, a key element of the transduction apparatus, will be determined. (4) Finally, a combination of approaches will be applied to further characterize and eventually identify the elusive transduction channel.
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