Molecular mechanism of prestin electromotive signal amplification

Ge, Jingpeng; Elferich, Johannes; Dehghani-Ghahnaviyeh, Sepehr; Zhao, Zhiyu; Meadows, Marc; Gersdorff, Henrique von; Tajkhorshid, Emad; Gouaux, Eric

doi:10.1016/j.cell.2021.07.034

Cited by 80 publications

(144 citation statements)

References 105 publications

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“…Dielectric loss may have its basis in the interaction of prestin with the viscous plasma membrane where it resides. Recent cryo-EM studies, including our own, on prestin have found significant interactions of membrane lipid around and within protein helices (Bavi et al, 2021;Butan et al, 2021;Ge et al, 2021) that confirms expectations from earlier physiological studies (Santos-Sacchi and Wu, 2004;Sfondouris et al, 2008;Fang et al, 2010;Zhai et al, 2020).…”

Section: Introductionsupporting

confidence: 84%

Phase tracking algorithms detect both real and imaginary components of outer hair cell nonlinear membrane capacitance that exhibits dielectric loss

Santos‐Sacchi

2022

Preprint

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Outer hair cell (OHC) nonlinear membrane capacitance (NLC) represents voltage-dependent sensor charge movements within prestin (SLC26a5) that drive OHC electromotility. Dielectric loss, a shift in charge movement phase from purely capacitive to resistive, is likely indicative of prestin interaction with the viscous lipid bilayer and has been suggested to correspond to prestin power output. The frequency response of NLC in OHC membrane patches has been measured with phase tracking and complex capacitance methodologies. While the latter approach can directly determine the presence of dielectric loss by assessing charge movement both in and out of phase with driving voltage, the former has been suggested to fail in this regard. Here we show that standard phase tracking in the presence of dielectric loss does indeed register this loss. Such estimates of NLC correspond to the absolute magnitude of complex NLC, indicating that total charge movement regardless of phase is assessed, thereby validating past and present measures of NLC frequency response that limits its effectiveness at high frequencies. This observation has important implications for understanding the role of prestin in cochlear amplification.

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Section: Introductionsupporting

confidence: 84%

Phase tracking algorithms detect both real and imaginary components of outer hair cell nonlinear membrane capacitance that exhibits dielectric loss

Santos‐Sacchi

2022

Preprint

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“…Over the frequency range of human hearing, voltage-driven electro-motility is imparted by expression of the transmembrane protein prestin [2,3] through a mechanism that couples electrical charge displacement in the prestin-membrane motor complex to changes in cell length. The structure of prestin [4][5][6] suggests OHC piezoelectricity arises on the whole-cell level from a large number of prestin molecules undergoing conformational changes on the nanoscale, with each conformational change involving an electrical charge displacement and a change in membrane area. But this mechanism might not extend beyond the range of human hearing to species with ultrasonic hearing.…”

Section: Introductionmentioning

confidence: 99%

Analysis of outer hair cell electromechanics reveals power delivery at the upper-frequency limits of hearing

Rabbitt

2022

J. R. Soc. Interface.

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Outer hair cells are the cellular motors in the mammalian inner ear responsible for sensitive high-frequency hearing. Motor function over the frequency range of human hearing requires expression of the protein prestin in the OHC lateral membrane, which imparts piezoelectric properties to the cell membrane. In the present report, electrical power consumption and mechanical power output of the OHC membrane–motor complex are determined using previously published voltage-clamp data from isolated OHCs and membrane patches. Results reveal that power output peaks at a best frequency much higher than implied by the low-pass character of nonlinear capacitance, and much higher than the whole-cell resistive–capacitive corner frequency. High frequency power output is enabled by a −90° shift in the phase of electrical charge displacement in the membrane, manifested electrically as emergence of imaginary-valued nonlinear capacitance.

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“…In vitro elucidation of the molecular bases of mechanosensation presents unique technical challenges and hearing is perhaps, at the biophysical level, the least understood of the senses. No fewer than three studies over the past year were released which employ cryo-EM to resolve states of prestin, an essential component of the cochlear amplifier [33][34][35]. Prestin is a member of the solute carrier 26 (SLC26) anion transporter family and functions as the electromotive molecule of outer hair cells (OHCs) which amplify incident sound waves.…”

Section: Cryo-electron Microscopymentioning

confidence: 99%

New Horizons in Structural Biology of Membrane Proteins: Experimental Evaluation of the Role of Conformational Dynamics and Intrinsic Flexibility

2022

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A plethora of membrane proteins are found along the cell surface and on the convoluted labyrinth of membranes surrounding organelles. Since the advent of various structural biology techniques, a sub-population of these proteins has become accessible to investigation at near-atomic resolutions. The predominant bona fide methods for structure solution, X-ray crystallography and cryo-EM, provide high resolution in three-dimensional space at the cost of neglecting protein motions through time. Though structures provide various rigid snapshots, only an amorphous mechanistic understanding can be inferred from interpolations between these different static states. In this review, we discuss various techniques that have been utilized in observing dynamic conformational intermediaries that remain elusive from rigid structures. More specifically we discuss the application of structural techniques such as NMR, cryo-EM and X-ray crystallography in studying protein dynamics along with complementation by conformational trapping by specific binders such as antibodies. We finally showcase the strength of various biophysical techniques including FRET, EPR and computational approaches using a multitude of succinct examples from GPCRs, transporters and ion channels.

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Molecular mechanism of prestin electromotive signal amplification

Cited by 80 publications

References 105 publications

Phase tracking algorithms detect both real and imaginary components of outer hair cell nonlinear membrane capacitance that exhibits dielectric loss

Phase tracking algorithms detect both real and imaginary components of outer hair cell nonlinear membrane capacitance that exhibits dielectric loss

Analysis of outer hair cell electromechanics reveals power delivery at the upper-frequency limits of hearing

New Horizons in Structural Biology of Membrane Proteins: Experimental Evaluation of the Role of Conformational Dynamics and Intrinsic Flexibility

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