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Τετάρτη 13 Ιουνίου 2018

The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin

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 prestin electrical (NLC, Qp) and mechanical (eM) activity across frequencies under voltage clamp (whole cell and microchamber). We find 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 (2) time constant at Vh of 32.6 and 24.8 μs, respectively. As expected for voltage-dependent kinetics, voltage excitation away from Vh has a faster, flatter frequency response, with our fastest measured 2 for eM of 18.2 μs. Previous observations of ultrafast eM ( 2 μs) 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.

SIGNIFICANCE STATEMENT Of two types of hair cells within the organ of Corti, inner hair cells and outer hair cells, the latter evolved to boost sensitivity to sounds. Damage results in hearing loss of 40–60 dB, revealing amplification gains of 100–1000x that arise from voltage-dependent mechanical responses [electromotility (eM)]. eM, driven by the membrane protein prestin, may work beyond 70 kHz. However, this speed exceeds, by over an order of magnitude, kinetics of typical voltage-dependent membrane proteins. We find eM is actually low pass in nature, indicating that prestin bears kinetics typical of other membrane proteins. These observations highlight potential difficulties in providing sufficient amplification beyond a cutoff frequency near 20 kHz. Nevertheless, observed trade-offs in eM gain-bandwith may sustain cochlear amplification across frequency.



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