The essence of the internal ear's operation is mechanoelectrical transduction, the conversion of mechanical stimuli into electrical responses. In both the cochlea and the vestibular labyrinth, hair cells are the site of transduction: working through the ear's complex accessory structures, a sound or an acceleration deflects mechanoreceptive hair bundles and thereby elicits an electrical response in each stimulated hair cell. In the last decade and a half, in vitro studies on hair cells isolated from the internal ear have contributed enormously to our understanding of the mechanoelectrical transduction process. As a result of the successes of electrophysiological and biophysical approaches, the field of auditory neuroscience has now reached a point at which further elucidation of mechanoelectrical transduction is limited by our understanding of its biochemical basis. The proposed experiments are meant better to define the biochemical constituents of the hair bundle. Bundles will be isolated from the hair cells of bullfrogs and studied in vitro. A new, high-sensitivity technique for protein detection will be used to catalog the bundle's components, among which specific proteins will be distinguished by immunoblotting. The identified proteins will also be localized by immunohistochemistry. Two proteins of particular functional importance will be sought: calmodulin, which mediates the effects of calcium ions in many cells, and myosin, which might be involved in the hair cell's adaptation to prolonged stimuli. Myosin-like molecules will also be sought through a molecular-biological approach. Finally, an attempt will be made to produce a specific, high-affinity blocker for the transduction channel. This novel molecule will then be chemically coupled to the transduction channel and used to identify the channel molecule among the bundle's constituents. The long-term goal of this experimentation is twofold. First, the investigations are meant to determine the basis for the gating of ion channels by mechanical force. Although little is known about the channels involved in any mechanically responsive organ, the hair cell is the best understood mechanoreceptor and that most likely to yield insights into the fundamental nature of mechanosensitivity. The second motivation for studying transduction is to understand the normal composition and operation of hair bundles, and thus to gain insights into how ototoxic drugs affect transduction channels and how acoustical trauma deranges the hair bundle's cytoskeleton. Some twenty million Americans suffer from significant sensorineural hearing loss, which largely results from compromised hair cells. It is only from an improved understanding of the transduction process that rational strategies may be devised for the prevention and amelioration of aural disease.
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