Effect of General Anesthetics and Alcohols on Prestin (SLC26A5) Function

Abstract

Prestin is a membrane protein essential to the electromotility of outer-hair cells (OHC) in the cochlea. This protein with piezoelectric properties has shown sensitivity to changes in cell membrane physical properties. The presence of molecules which impact the lateral pressure or the fluidity of the membrane -such as cholesterol, NSAIDs or lipophilic ions- can alter the electrophysiological properties of prestin as well as the electromotility. In an OHC, the nonlinear capacitance (NLC) and the electromotility are both conferred by prestin and coupled. This allows monitoring the NLC as a surrogate measure of prestin's function.Here we describe the impact of general anesthetics and alcohols on prestin, and aim to use this protein as a model system for studying membrane-protein interaction through changes in the NLC. We tested the effect on prestin of alcohols with various C-chains (C2 to C10) and some general anesthetics (GA: propofol, isoflurane, halothane, chloroform, etomidate and xylazine). All the alcohols tested trigger a dose-dependent shift in the characteristic voltage at half-maximal charge transfer (V1/2), with the sensitivity increasing as the alcohols' carbon-chain is longer. The direction of the shift changes with concentration, the lower concentration cause a negative shift while higher concentrations shift V1/2 closer to 0mV. These shifts are correlated with changes in the linear capacitance of the cell. All of the GA we tested caused a dose-dependent increase in charge density at sub-millimolar concentrations as well as a shift of V1/2 toward hyperpolarized voltages. The sensitivity of prestin to these molecules seems to follow the Meyer/Overton correlation.The shift in the NLC as well as the increase in charge density can modify the function of the OHC at resting potential and alter cochlear amplification.