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Neurosci."],"published-print":{"date-parts":[[2023,4,5]]},"abstract":"<jats:p>Charged moieties in the outer hair cell (OHC) membrane motor protein, prestin, are driven by transmembrane voltage to power OHC electromotility (eM) and cochlear amplification (CA), an enhancement of mammalian hearing. Consequently, the speed of prestin's conformational switching constrains its dynamic influence on micromechanics of the cell and the organ of Corti. Corresponding voltage-sensor charge movements in prestin, classically assessed as a voltage-dependent, nonlinear membrane capacitance (NLC), have been used to gauge its frequency response, but have been validly measured only out to 30 kHz. Thus, controversy exists concerning the effectiveness of eM in supporting CA at ultrasonic frequencies where some mammals can hear. Using megahertz sampling of guinea pig (either sex) prestin charge movements, we extend interrogations of NLC into the ultrasonic range (up to 120 kHz) and find an order of magnitude larger response at 80 kHz than previously predicted, indicating that an influence of eM at ultrasonic frequencies is likely, in line with recent<jats:italic>in vivo<\/jats:italic>results (Levic et al., 2022). Given wider bandwidth interrogations, we also validate kinetic model predictions of prestin by directly observing its characteristic cut-off frequency under voltage-clamp as the intersection frequency (F<jats:sub>is<\/jats:sub>), near 19 kHz, of the real and imaginary components of complex NLC (cNLC). The frequency response of prestin displacement current noise determined from either the Nyquist relation or stationary measures aligns with this cut-off. We conclude that voltage stimulation accurately assesses the spectral limits of prestin activity, and that voltage-dependent conformational switching is physiologically significant in the ultrasonic range.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>The motor protein prestin powers outer hair cell (OHC) electromotility (eM) and cochlear amplification (CA), an enhancement of high-frequency mammalian hearing. The ability of prestin to work at very high frequencies depends on its membrane voltage-driven conformation switching. Using megahertz sampling, we extend measures of prestin charge movement into the ultrasonic range and find response magnitude at 80 kHz an order of magnitude larger than previously estimated, despite confirmation of previous low pass characteristic frequency cut-offs. The frequency response of prestin noise garnered by the admittance-based Nyquist relation or stationary noise measures confirms this characteristic cut-off frequency. Our data indicate that voltage perturbation provides accurate assessment of prestin performance indicating that it can support cochlear amplification into a higher frequency range than previously thought.<\/jats:p>","DOI":"10.1523\/jneurosci.2033-22.2023","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T18:50:12Z","timestamp":1677869412000},"page":"2460-2468","source":"Crossref","is-referenced-by-count":15,"title":["Megahertz Sampling of Prestin (SLC26a5) Voltage-Sensor Charge Movements in Outer Hair Cell Membranes Reveals Ultrasonic Activity that May Support Electromotility and Cochlear Amplification"],"prefix":"10.1523","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8274-7751","authenticated-orcid":false,"given":"Joseph","family":"Santos-Sacchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Ping","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhasakumar","family":"Navaratnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"key":"2023041803562819000_43.14.2460.1","doi-asserted-by":"crossref","first-page":"7306","DOI":"10.1103\/PhysRevB.44.7306","article-title":"Relationship between the time-domain Kohlrausch-Williams-Watts and frequency-domain Havriliak-Negami relaxation functions","volume":"44","author":"Alverez","year":"1991","journal-title":"Phys Rev B"},{"key":"2023041803562819000_43.14.2460.2","doi-asserted-by":"crossref","first-page":"46619","DOI":"10.1038\/srep46619","article-title":"Current carried by the Slc26 family member prestin does not flow through the transporter pathway","volume":"7","author":"Bai","year":"2017","journal-title":"Sci Rep"},{"key":"2023041803562819000_43.14.2460.3","doi-asserted-by":"crossref","first-page":"16460","DOI":"10.1038\/s41598-019-52965-1","article-title":"Prestin kinetics and corresponding frequency dependence augment during early development of the outer hair cell within the mouse organ of Corti","volume":"9","author":"Bai","year":"2019","journal-title":"Sci Rep"},{"key":"2023041803562819000_43.14.2460.4","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/s41586-021-04152-4","article-title":"The conformational cycle of prestin underlies outer-hair cell electromotility","volume":"600","author":"Bavi","year":"2021","journal-title":"Nature"},{"key":"2023041803562819000_43.14.2460.5","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.199034"},{"key":"2023041803562819000_43.14.2460.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.3966153"},{"key":"2023041803562819000_43.14.2460.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27915-z"},{"key":"2023041803562819000_43.14.2460.8","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRev.86.702"},{"key":"2023041803562819000_43.14.2460.9","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1016\/j.bpj.2021.08.015","article-title":"Gating current noise produced by Brownian models of a voltage sensor","volume":"120","author":"Catacuzzeno","year":"2021","journal-title":"Biophys J"},{"key":"2023041803562819000_43.14.2460.10","unstructured":"Cole KS (1971) Some aspects of electrical studies of the squid giant axon membrane. 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