PHARMACOLOGICAL ANALYSIS OF IONIC BALANCE IN HAIR CELLS

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DESCRIPTION: The proper function of hair cells, the sensory transducing cells of the auditory and vestibular systems, depends on proper ionic compositions both extracellular and intracellular. Several forms of hair cell injury and loss of function (e.g., acoustic overstimulation, Meniere's Disease, aging) may result from loss of proper ionic balance. The long-term objective is to determine how hair cells regulate their intracellular ionic status. Understanding these regulatory processes may eventually help to prevent or to minimize some forms of hearing loss. Previously in this project, the major cellular processes of ionic balance, and the net transport rates under control conditions, were determined for isolated goldfish hair cells. In one aim, a combination of experimental methods (electron-probe microanalysis, microfluorometry, and quantitative microscopy) and theoretical analysis will be used to determine how these processes work together in the intact cell. An examination of how transport rates and solute contents change after different disturbances of ion-transport processes will be conducted. An inference from the results of specific major interactions among the solutes and the regulatory processes involved in the maintenance of the steady state of the cell will be made. Such predicted interactions will be tested in further experiments. A second aim extends the analysis of ion balance to a more natural state: hair cells with apically located transduction channels open will be examined under conditions of a different fluids bathing the apical versus the basolateral surfaces of these cells, as is the case in vivo. The proposal will test hypotheses about how the presence of these channels and the composition of the endolymphatic fluid that bathes them may affect the dynamics of ion regulation. Further, this experimental approach will be used for further tests of interactions among solute-transport processes. A third aim will test the hypothesis that mammalian outer hair cells have a difficulty in meeting some acid/base challenges, perhaps due to their membrane specializations for auditory transduction. It was found that a surprisingly high fraction of the metabolic load of goldfish hair cells is devoted to regulating acid/base balance. Theoretical studies suggest that there may be an advantage to having a high rate of leaking and pumping acid. If so, then mammalian (guinea-pig) outer hair cells do not seem to have this advantage. These studies will determine the acid-handling characteristics of several types of hair cells, to see if mammalian outer hair cells are particularly sensitive to certain types of challenges to ionic balance.