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Article ; Online: Physiology and biophysics of outer hair cells: The cells of Dallos.

Santos-Sacchi, Joseph / Navaratnam, Dhasakumar

2022 Volume 423, Page(s) 108525

Abstract: The outer hair cell (OHC) is celebrated on the 21st birthday of prestin's identification and the year of this molecular motor's sub-nanometer structural solution. Dogmatic conceptions of OHC performance have been challenged by decades of biophysical ... ...

Abstract	The outer hair cell (OHC) is celebrated on the 21st birthday of prestin's identification and the year of this molecular motor's sub-nanometer structural solution. Dogmatic conceptions of OHC performance have been challenged by decades of biophysical interrogations that must be influential on hearing, but which have received little attention by cochlear modelers. Here we point to these interrogations and present a compilation of articles in a Special Issue of Hearing Research that reconsiders the OHC's role in cochlear amplification, as well as the cell's basic physiology. We are getting closer to understanding these special cells of Dallos.
MeSH term(s)	Biophysics ; Cochlea/physiology ; Hair Cells, Auditory, Outer/physiology ; Hair Cells, Vestibular ; Hearing/physiology
Language	English
Publishing date	2022-05-16
Publishing country	Netherlands
Document type	Editorial
ZDB-ID	282629-x
ISSN	1878-5891 ; 0378-5955
ISSN (online)	1878-5891
ISSN	0378-5955
DOI	10.1016/j.heares.2022.108525
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Article ; Online: On the frequency response of prestin charge movement in membrane patches.

Santos-Sacchi, Joseph / Tan, Winston

Biophysical journal

2022 Volume 121, Issue 12, Page(s) 2371–2379

Abstract: Outer hair cell (OHC) nonlinear membrane capacitance derives from voltage-dependent sensor charge movements within the membrane protein prestin (SLC26a5) that drive OHC electromotility. The ability of the protein to influence hearing depends on its ... ...

Abstract	Outer hair cell (OHC) nonlinear membrane capacitance derives from voltage-dependent sensor charge movements within the membrane protein prestin (SLC26a5) that drive OHC electromotility. The ability of the protein to influence hearing depends on its reaction to membrane receptor potentials across auditory frequency. Estimates of prestin's frequency response have been evaluated by several groups out to tens of kHz in voltage-clamped macro-patches of OHC membrane. The response is a power function of frequency that is down 40 dB at 77 kHz. Despite these observations, concerns remain that the macro-patch approach is flawed due to mechanical constraints of pipette solution column load or patch size itself. In the absence of these influences, prestin's frequency response is posited by some to be ultrasonic in nature. Here we evaluate the influence of these putative confounding factors on prestin's frequency response. We show that neither pipette column height nor negative or positive pipette pressure substantially influence total sensor charge frequency response. Additionally, patch surface area has negligible influence. We conclude that the speed of voltage-driven conformational changes in prestin within the plasma membrane is accurately assessed with the macro-patch technique, permitting investigations of membrane characteristics that can substantially alter prestin's performance bandwidth. We illustrate significant alterations in bandwidth by perturbation of membrane fluidity and chloride anion concentration. Finally, we speculate that OHC membrane characteristics may differ along the tonotopic axis of the cochlea to tune nonlinear membrane capacitance frequency cutoffs.
MeSH term(s)	Cell Membrane/metabolism ; Electric Capacitance ; Hair Cells, Auditory, Outer/metabolism ; Membrane Potentials/physiology ; Patch-Clamp Techniques ; Proteins/metabolism
Chemical Substances	Proteins
Language	English
Publishing date	2022-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2022.05.020
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Correction: Outer hair cell electromotility is low-pass filtered relative to the molecular conformational changes that produce nonlinear capacitance.

Santos-Sacchi, Joseph / Iwasa, Kuni H / Tan, Winston

The Journal of general physiology

2023 Volume 156, Issue 1

Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Published Erratum
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.20181228012112023c
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Article ; Online: Megahertz Sampling of Prestin (SLC26a5) Voltage-Sensor Charge Movements in Outer Hair Cell Membranes Reveals Ultrasonic Activity that May Support Electromotility and Cochlear Amplification.

Santos-Sacchi, Joseph / Bai, Jun-Ping / Navaratnam, Dhasakumar

The Journal of neuroscience : the official journal of the Society for Neuroscience

2023 Volume 43, Issue 14, Page(s) 2460–2468

Abstract: 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' ... ...

Abstract	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
MeSH term(s)	Animals ; Guinea Pigs ; Ultrasonics ; Hair Cells, Auditory, Outer/physiology ; Cochlea ; Hearing ; Cell Membrane/metabolism ; Mammals
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2033-22.2023
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Article ; Online: Complex nonlinear capacitance in outer hair cell macro-patches: effects of membrane tension.

Santos-Sacchi, Joseph / Tan, Winston

Scientific reports

2020 Volume 10, Issue 1, Page(s) 6222

Abstract: Outer hair cell (OHC) nonlinear capacitance (NLC) represents voltage sensor charge movements of prestin (SLC26a5), the protein responsible for OHC electromotility. Previous measures of NLC frequency response have employed methods which did not assess the ...

Abstract	Outer hair cell (OHC) nonlinear capacitance (NLC) represents voltage sensor charge movements of prestin (SLC26a5), the protein responsible for OHC electromotility. Previous measures of NLC frequency response have employed methods which did not assess the influence of dielectric loss (sensor charge movements out of phase with voltage) that may occur, and such loss conceivably may influence prestin's frequency dependent activity. Here we evaluate prestin's complex capacitance out to 30 kHz and find that prestin's frequency response determined using this approach coincides with all previous estimates. We also show that membrane tension has no effect on prestin's frequency response, despite substantial shifts in its voltage operating range, indicating that prestin transition rate alterations do not account for the shifts. The magnitude roll-off of prestin activity across frequency surpasses the reductions of NLC caused by salicylate treatments that are known to abolish cochlear amplification. Such roll-off likely limits the effectiveness of prestin in contributing to cochlear amplification at the very high acoustic frequencies processed by some mammals.
MeSH term(s)	Animals ; Cells, Cultured ; Electric Capacitance ; Guinea Pigs ; Hair Cells, Auditory, Outer/cytology ; Hair Cells, Auditory, Outer/drug effects ; Hair Cells, Auditory, Outer/metabolism ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Patch-Clamp Techniques ; Primary Cell Culture ; Proteins/metabolism ; Salicylates/pharmacology
Chemical Substances	Pres protein, Cavia porcellus ; Proteins ; Salicylates
Language	English
Publishing date	2020-04-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-63201-6
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Article ; Online: Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress

Tan, Winston J. T. / Santos-Sacchi, Joseph / Tonello, Jane / Shanker, Anil / Ivanova, Alla V.

Antioxidants. 2023 June 06, v. 12, no. 6

2023

Abstract: Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed ... ...

Abstract	Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic–pituitary–adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.
Keywords	cytoskeleton ; energy ; energy metabolism ; females ; gene expression ; glycolysis ; mitochondria ; models ; oxidative stress ; rapamycin
Language	English
Dates of publication	2023-0606
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12061225
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: State dependent effects on the frequency response of prestin's real and imaginary components of nonlinear capacitance.

Santos-Sacchi, Joseph / Navaratnam, Dhasakumar / Tan, Winston J T

Scientific reports

2021 Volume 11, Issue 1, Page(s) 16149

Abstract: The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin (SLC26a5), in high density, whose charge movement is evidenced as a nonlinear capacitance (NLC). NLC is bell-shaped, with its peak occurring at a voltage, ... ...

Abstract	The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin (SLC26a5), in high density, whose charge movement is evidenced as a nonlinear capacitance (NLC). NLC is bell-shaped, with its peak occurring at a voltage, V
MeSH term(s)	Acoustic Stimulation ; Animals ; Cochlea/physiology ; Electric Capacitance ; Guinea Pigs ; Hair Cells, Auditory, Outer/physiology ; Kinetics ; Mechanotransduction, Cellular/physiology ; Membrane Potentials/physiology ; Models, Biological ; Nonlinear Dynamics ; Patch-Clamp Techniques ; Protein Conformation ; Proteins/chemistry ; Proteins/physiology
Chemical Substances	Pres protein, Cavia porcellus ; Proteins
Language	English
Publishing date	2021-08-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-95121-4
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Article ; Online: Voltage Does Not Drive Prestin (SLC26a5) Electro-Mechanical Activity at High Frequencies Where Cochlear Amplification Is Best.

Santos-Sacchi, Joseph / Tan, Winston

iScience

2019 Volume 22, Page(s) 392–399

Abstract: Cochlear amplification denotes a boost to auditory sensitivity and selectivity that is dependent on outer hair cells from Corti's organ. Voltage-driven electromotility of the cell is believed to feed energy back into the cochlear partition via a cycle-by- ...

Abstract	Cochlear amplification denotes a boost to auditory sensitivity and selectivity that is dependent on outer hair cells from Corti's organ. Voltage-driven electromotility of the cell is believed to feed energy back into the cochlear partition via a cycle-by-cycle mechanism at very high acoustic frequencies. Here we show using wide-band macro-patch voltage-clamp to drive prestin, the molecular motor underlying electromotility, that its voltage-sensor charge movement is unusually low pass in nature, being incapable of following high-frequency voltage changes. Our data are incompatible with a cycle-by-cycle mechanism responsible for high-frequency tuning in mammals.
Language	English
Publishing date	2019-11-25
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2019.11.036
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Article: Chloride binding and cholesterol effects on high frequency complex nonlinear capacitance (cNLC) in the mouse outer hair cell: experiment and molecular dynamics.

Bai, Jun-Ping / Zhang, Chenou / Renigunta, Vijay / Oliver, Dominik / Navaratnam, Dhasakumar / Beckstein, Oliver / Santos-Sacchi, Joseph

bioRxiv : the preprint server for biology

2024

Abstract: The function of prestin (SLC26a5), an anion transport family member, has evolved to enhance auditory sensitivity and frequency selectivity by providing mechanical feedback via outer hair cells (OHC) into the organ of Corti. The frequency extent of this ... ...

Abstract	The function of prestin (SLC26a5), an anion transport family member, has evolved to enhance auditory sensitivity and frequency selectivity by providing mechanical feedback via outer hair cells (OHC) into the organ of Corti. The frequency extent of this boost is governed by the voltage-dependent kinetics of the protein's charge movements, otherwise known as nonlinear capacitance (NLC) that we measure in membrane patches under voltage clamp. Here we extend our previous studies on guinea pig OHCs by studying the frequency response of NLC in the mouse OHC, a species with higher frequency auditory needs. We find that the characteristic frequency cut-off (F Significance: Prestin is believed to provide cochlear amplification in mammals that possess a wide range of frequency sensitivities, yet its tertiary structure is indistinguishable among those species studied. We find that prestin kinetics is faster in mice than in guinea pigs, mice showing higher frequency auditory capabilities. Chloride binding is not influential, but membrane lipids/viscosity is. We suggest that the evolution of prestin's species performance involves modifications of impinging loads, not the protein itself.
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.29.577264
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Article ; Online: Coupling between outer hair cell electromotility and prestin sensor charge depends on voltage operating point.

Santos-Sacchi, Joseph / Tan, Winston J T

Hearing research

2021 Volume 423, Page(s) 108373

Abstract: The OHC drives cochlear amplification, and prestin activity is the basis. The frequency response of nonlinear capacitance (NLC), which is a ratiometric measure of prestin's voltage-sensor charge movement ( ... ...

Abstract	The OHC drives cochlear amplification, and prestin activity is the basis. The frequency response of nonlinear capacitance (NLC), which is a ratiometric measure of prestin's voltage-sensor charge movement (dQ
MeSH term(s)	Cochlea ; Electric Capacitance ; Hair Cells, Auditory, Outer/physiology ; Hair Cells, Vestibular ; Patch-Clamp Techniques
Language	English
Publishing date	2021-10-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	282629-x
ISSN	1878-5891 ; 0378-5955
ISSN (online)	1878-5891
ISSN	0378-5955
DOI	10.1016/j.heares.2021.108373
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