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On Membrane Motor Activity and Chloride Flux in the Outer Hair Cell: Lessons Learned from the Environmental Toxin Tributyltin

Lei Song ^* , Achim Seeger  and Joseph Santos-Sacchi ^*  

Otolaryngology,^* Neurobiology, and Surgery, Yale University School of Medicine, New Haven, Connecticut

Correspondence: Address reprint requests to Joseph Santos-Sacchi, Sections of Otolaryngology and Neurobiology, Yale University School of Medicine, BML 246, 333 Cedar St., New Haven, CT 06510. Tel.: 203-785-5407; Fax: 203-737-2502; E-mail: joseph.santos-sacchi{at}yale.edu.

The outer hair cell (OHC) underlies mammalian cochlea amplification, and its lateral membrane motor, prestin, which drives the cell's mechanical activity, is modulated by intracellular chloride ions. We have previously described a native nonselective conductance (G_metL) that influences OHC motor activity via Cl flux across the lateral membrane. Here we further investigate this conductance and use the environmental toxin tributyltin (TBT) to better understand Cl-prestin interactions. Capitalizing on measures of prestin-derived nonlinear capacitance to gauge Cl flux across the lateral membrane, we show that the Cl ionophore TBT, which affects neither the motor nor G_metL directly, is capable of augmenting the native flux of Cl in OHCs. These observations were confirmed using the chloride-sensitive dye MQAE. Furthermore, the compound's potent ability, at nanomolar concentrations, to equilibrate intra- and extracellular Cl concentrations is shown to surpass the effectiveness of G_metL in promoting Cl flux, and secure a quantitative analysis of Cl-prestin interactions in intact OHCs. Using malate as an anion replacement, we quantify chloride effects on the nonlinear charge density and operating voltage range of prestin. Our data additionally suggest that ototoxic effects of organotins can derive from their disruption of OHC Cl homeostasis, ultimately interfering with anionic modulation of the mammalian cochlear amplifier. Notably, this observation identifies a new environmental threat for marine mammals by TBT, which is known to accumulate in the food chain.

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