The frequency response of outer hair cell voltage-dependent motility is limited by kinetics of prestin

Abstract

The voltage-dependent protein SLC26a5 (prestin) underlies outer hair cell electromotility (eM), which is responsible for cochlear amplification in mammals. The electrical signature of eM is a bell-shaped nonlinear capacitance (NLC), deriving from prestin sensor-charge (Qp) movements, which peaks at the membrane voltage, Vh, where charge is distributed equally on either side of the membrane. Voltage dependencies of NLC and eM differ depending on interrogation frequency and intracellular chloride, revealing slow intermediate conformational transitions between anion binding and voltage-driven Qp movements. Consequently, NLC exhibits low-pass characteristics, substantially below prevailing estimates of eM frequency response. Here we study in guinea pig and mouse of either sex synchronous prestinelectrical (NLC, Qp) andmechanical (eM) activityacross frequencies under voltageclamp(wholecell andmicrochamber). Wefind that eM and Qp magnitude and phase correspond, indicating tight piezoelectric coupling. Electromechanical measures (both NLC and eM) show dual-Lorentzian, low-pass behavior, with a limiting (T2) time constant at Vh of 32.6 and 24.8 s, respectively. As expected for voltage-dependent kinetics, voltage excitation away from Vh has a faster, flatter frequency response, with our fastest measured T2 for eM of 18.2 s. Previous observations of ultrafast eM (T ~ 2 s) were obtained at offsets far removed from Vh. We hypothesize that trade-offs in eM gain-bandwith arising from voltage excitation at membrane potentials offset from Vh influence the effectiveness of cochlear amplification across frequencies.