2023
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 J, Bai J, Navaratnam D. Megahertz Sampling of Prestin (SLC26a5) Voltage-Sensor Charge Movements in Outer Hair Cell Membranes Reveals Ultrasonic Activity that May Support Electromotility and Cochlear Amplification. Journal Of Neuroscience 2023, 43: 2460-2468. PMID: 36868859, PMCID: PMC10082455, DOI: 10.1523/jneurosci.2033-22.2023.Peer-Reviewed Original ResearchConceptsConformational switchingMammalian hearingMembrane motor proteinCochlear amplificationMotor protein prestinVoltage-sensor charge movementOuter hair cell electromotilityHair cell electromotilityProtein prestinMotor proteinsConformation switchingCharge movementPrestinPrestin activityCell membraneOHC electromotilityHair cell membraneElectromotilityTransmembrane voltageOrgan of CortiAmplificationMammalsMembrane capacitanceProtein
2022
Outer hair cell function is normal in βV spectrin knockout mice
Stankewich MC, Bai JP, Stabach PR, Khan S, Tan WJT, Surguchev A, Song L, Morrow JS, Santos-Sacchi J, Navaratnam DS. Outer hair cell function is normal in βV spectrin knockout mice. Hearing Research 2022, 423: 108564. PMID: 35864018, DOI: 10.1016/j.heares.2022.108564.Peer-Reviewed Original ResearchConceptsOuter hair cellsAuditory brainstem response wavesAuditory thresholdOuter hair cell functionSpiral ganglion neuronsEfferent nerve fibersHair cell functionNumber of afferentsGanglion neuronsNerve fibersKnockout miceNeuronal structuresMiceHair cellsCell functionElectromechanical activityPutative roleType IOngoing investigationExon deletionsSynaptopathyAfferentsData supportResponse wavesNeuronsSingle particle cryo-EM structure of the outer hair cell motor protein prestin
Butan C, Song Q, Bai JP, Tan WJT, Navaratnam D, Santos-Sacchi J. Single particle cryo-EM structure of the outer hair cell motor protein prestin. Nature Communications 2022, 13: 290. PMID: 35022426, PMCID: PMC8755724, DOI: 10.1038/s41467-021-27915-z.Peer-Reviewed Original ResearchConceptsTransmembrane domainProtein prestinSingle-particle cryo-EM structuresAnti-sigma factor antagonist domainOuter hair cell motor protein prestinCryo-EM structureCryo-electron microscopyMotor protein prestinSLC26 family membersSulfate transportersTransmembrane segmentsPrestin functionÅ resolutionPrestinOHC electromotilityOpen stateCochlear amplificationPutative mechanismsFamily membersDomainRepeatsSLC26A9TransportersMutationsElectromotility
2021
Genes related to SNPs identified by Genome-wide association studies of age-related hearing loss show restriction to specific cell types in the adult mouse cochlea
Xue N, Song L, Song Q, Santos-Sacchi J, Wu H, Navaratnam D. Genes related to SNPs identified by Genome-wide association studies of age-related hearing loss show restriction to specific cell types in the adult mouse cochlea. Hearing Research 2021, 410: 108347. PMID: 34536825, DOI: 10.1016/j.heares.2021.108347.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingApical cell polarityGenome-wide association studiesAdult mouse cochleaSpecific cell typesCell polaritySubtypes of cellsSignificant genetic componentSingle nucleotide polymorphismsVesicle recyclingRNA sequencingAssociation studiesGenesVarying ExpressionCell typesGenetic componentNucleotide polymorphismsSNPsMouse cochleaCell functionGenesetsHair cellsHair cell functionSignificant overlapExpressionThe naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology
Buffenstein R, Amoroso V, Andziak B, Avdieiev S, Azpurua J, Barker AJ, Bennett NC, Brieño‐Enríquez M, Bronner GN, Coen C, Delaney MA, Dengler‐Crish C, Edrey YH, Faulkes CG, Frankel D, Friedlander G, Gibney PA, Gorbunova V, Hine C, Holmes MM, Jarvis JUM, Kawamura Y, Kutsukake N, Kenyon C, Khaled WT, Kikusui T, Kissil J, Lagestee S, Larson J, Lauer A, Lavrenchenko LA, Lee A, Levitt JB, Lewin GR, Hardell K, Lin TD, Mason MJ, McCloskey D, McMahon M, Miura K, Mogi K, Narayan V, O'Connor TP, Okanoya K, O'Riain MJ, Park TJ, Place NJ, Podshivalova K, Pamenter ME, Pyott SJ, Reznick J, Ruby JG, Salmon AB, Santos‐Sacchi J, Sarko DK, Seluanov A, Shepard A, Smith M, Storey KB, Tian X, Vice EN, Viltard M, Watarai A, Wywial E, Yamakawa M, Zemlemerova ED, Zions M, St. John Smith E. The naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology. Biological Reviews 2021, 97: 115-140. PMID: 34476892, PMCID: PMC9277573, DOI: 10.1111/brv.12791.Peer-Reviewed Original ResearchState dependent effects on the frequency response of prestin’s real and imaginary components of nonlinear capacitance
Santos-Sacchi J, Navaratnam D, Tan WJT. State dependent effects on the frequency response of prestin’s real and imaginary components of nonlinear capacitance. Scientific Reports 2021, 11: 16149. PMID: 34373481, PMCID: PMC8352928, DOI: 10.1038/s41598-021-95121-4.Peer-Reviewed Original ResearchEfferent feedback controls bilateral auditory spontaneous activity
Wang Y, Sanghvi M, Gribizis A, Zhang Y, Song L, Morley B, Barson DG, Santos-Sacchi J, Navaratnam D, Crair M. Efferent feedback controls bilateral auditory spontaneous activity. Nature Communications 2021, 12: 2449. PMID: 33907194, PMCID: PMC8079389, DOI: 10.1038/s41467-021-22796-8.Peer-Reviewed Original ResearchConceptsSpontaneous activityEfferent modulationEfferent pathwaysMedial olivocochlear systemCentral nervous systemCentral auditory systemInner hair cellsAuditory systemNicotinic acetylcholine receptorsSpontaneous activity patternsOlivocochlear systemHearing onsetEfferent systemChemogenetic experimentsBilateral couplingNervous systemAcetylcholine receptorsCircuit formationEfferent feedbackFiring patternsHair cellsΑ9/Auditory sensitivityBilateral correlationActivity patternsComprehensive somatosensory and neurological phenotyping of NCS1 knockout mice
Nguyen LD, Nolte LG, Tan WJT, Giuvelis D, Santos-Sacchi J, Bilsky E, Ehrlich BE. Comprehensive somatosensory and neurological phenotyping of NCS1 knockout mice. Scientific Reports 2021, 11: 2372. PMID: 33504822, PMCID: PMC7840744, DOI: 10.1038/s41598-021-81650-5.Peer-Reviewed Original ResearchConceptsNeuronal calcium sensor-1Peripheral nervous systemNervous systemMale miceKnockout micePaclitaxel-induced peripheral neuropathyKO modelKO male miceNCS1 expressionMammalian nervous systemPrecise physiological significanceSex-specific effectsPeripheral neuropathyFemale miceModulatory roleBehavioral testsPharmacological targetsMiceNeurodegenerative diseasesClinical interestMemory acquisitionMotor performancePathological statesAffective behaviorDisease
2020
Functional, Morphological, and Evolutionary Characterization of Hearing in Subterranean, Eusocial African Mole-Rats
Pyott SJ, van Tuinen M, Screven LA, Schrode KM, Bai JP, Barone CM, Price SD, Lysakowski A, Sanderford M, Kumar S, Santos-Sacchi J, Lauer AM, Park TJ. Functional, Morphological, and Evolutionary Characterization of Hearing in Subterranean, Eusocial African Mole-Rats. Current Biology 2020, 30: 4329-4341.e4. PMID: 32888484, PMCID: PMC8109146, DOI: 10.1016/j.cub.2020.08.035.Peer-Reviewed Original ResearchConceptsHair bundle morphologyAmino acid substitutionsAltered hearingLink proteinAcid substitutionsUnique evolutionary trajectoryMolecular evolutionary analysisCochlear amplificationEvolutionary characterizationEvolutionary analysisHuman hearing lossEvolutionary trajectoriesBundle morphologyPrestin functionAfrican Mole-RatsCodon levelSelection pressureSubterranean lifestyleSubterranean rodentsMole-RatUnique lifestyleProteinHair cellsSpeciesOuter hair cellsCalcium‐induced calcium release in proximity to hair cell BK channels revealed by PKA activation
Bai J, Xue N, Lawal O, Nyati A, Santos‐Sacchi J, Navaratnam D. Calcium‐induced calcium release in proximity to hair cell BK channels revealed by PKA activation. Physiological Reports 2020, 8: e14449. PMID: 32748549, PMCID: PMC7399380, DOI: 10.14814/phy2.14449.Peer-Reviewed Original ResearchConceptsBK channelsBK currentsCalcium-activated potassium channelsLarge-conductance calcium-activated potassium channelsCalcium-induced calcium releaseEntry of CaSlo subunitSynaptic releaseCalcium releaseChicken hair cellsPotassium channelsHair cellsIP3 receptorCICRA ActivationPKA activationActivationCritical roleImagingReleaseRyanodineComplex nonlinear capacitance in outer hair cell macro-patches: effects of membrane tension
Santos-Sacchi J, Tan W. Complex nonlinear capacitance in outer hair cell macro-patches: effects of membrane tension. Scientific Reports 2020, 10: 6222. PMID: 32277153, PMCID: PMC7148382, DOI: 10.1038/s41598-020-63201-6.Peer-Reviewed Original ResearchMaturation of Voltage-induced Shifts in SLC26a5 (Prestin) Operating Point during Trafficking and Membrane Insertion
Zhai F, Song L, Bai JP, Dai C, Navaratnam D, Santos-Sacchi J. Maturation of Voltage-induced Shifts in SLC26a5 (Prestin) Operating Point during Trafficking and Membrane Insertion. Neuroscience 2020, 431: 128-133. PMID: 32061780, PMCID: PMC8720582, DOI: 10.1016/j.neuroscience.2020.02.003.Peer-Reviewed Original ResearchConceptsMembrane motor proteinVoltage-dependent proteinsMembrane insertionOuter hair cellsMotor proteinsPrestin densityHEK cell linesConformational changesBiophysical forcesOHC electromotilityProteinCell linesMembrane potentialCooperative interactionsPrestinHair cellsCochlear amplificationTransmembrane voltageNonlinear capacitanceMammalsTraffickingVoltage-induced shiftElectromotilityMaturationMembrane
2019
Prestin kinetics and corresponding frequency dependence augment during early development of the outer hair cell within the mouse organ of Corti
Bai JP, Navaratnam D, Santos-Sacchi J. Prestin kinetics and corresponding frequency dependence augment during early development of the outer hair cell within the mouse organ of Corti. Scientific Reports 2019, 9: 16460. PMID: 31712635, PMCID: PMC6848539, DOI: 10.1038/s41598-019-52965-1.Peer-Reviewed Original ResearchConceptsOuter hair cellsPostnatal dayVoltage-sensor charge movementAltricial animalsPostnatal developmentCochlear placeElectrical correlatesHair cellsMouse organsCochlear amplificationEarly developmentAuditory frequencyPrestin activityAuditory capabilitiesCellsCharge movementHigh frequencyResponse increasesPrestin functionMiceActivityMonthsCourseOuter hair cell electromotility is low-pass filtered relative to the molecular conformational changes that produce nonlinear capacitance
Santos-Sacchi J, Iwasa KH, Tan W. Outer hair cell electromotility is low-pass filtered relative to the molecular conformational changes that produce nonlinear capacitance. The Journal Of General Physiology 2019, 151: 1369-1385. PMID: 31676485, PMCID: PMC6888751, DOI: 10.1085/jgp.201812280.Peer-Reviewed Original ResearchModulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice
El-Hassar L, Song L, Tan WJT, Large CH, Alvaro G, Santos-Sacchi J, Kaczmarek LK. Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice. Journal Of Neuroscience 2019, 39: 4797-4813. PMID: 30936239, PMCID: PMC6561694, DOI: 10.1523/jneurosci.0839-18.2019.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAuditory PathwaysAuditory PerceptionBrain StemCochlear NucleusElectrophysiological PhenomenaEvoked Potentials, Auditory, Brain StemFemaleFragile X Mental Retardation ProteinFragile X SyndromeHydantoinsIn Vitro TechniquesMaleMiceMice, KnockoutPatch-Clamp TechniquesPyridinesShaw Potassium ChannelsConceptsAuditory brainstem responseWild-type animalsRepetitive firingABR wave ICurrent-clamp recordingsAuditory brainstem nucleiVoltage-clamp recordingsHigh-frequency firingSingle action potentialFragile X syndromeTrapezoid bodyBrainstem nucleiBrainstem responseMedial nucleusAuditory brainstemAuditory nerveWave IWave IVAction potentialsSensory stimuliKv3.1 channelsCentral processingMental retardation proteinHigh sound levelsMiceThe speed limit of outer hair cell electromechanical activity
Santos-Sacchi J. The speed limit of outer hair cell electromechanical activity. HNO 2019, 67: 159-164. PMID: 30747242, DOI: 10.1007/s00106-019-0615-9.Peer-Reviewed Original Research
2018
The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin
Santos-Sacchi J, Tan W. The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin. Journal Of Neuroscience 2018, 38: 5495-5506. PMID: 29899032, PMCID: PMC6001036, DOI: 10.1523/jneurosci.0425-18.2018.Peer-Reviewed Original ResearchConceptsFrequency responseVoltage excitationNonlinear capacitanceFlat frequency responseLow-pass behaviorInterrogation frequencyMechanical responsePiezoelectric couplingCutoff frequencyLow-pass characteristicsLow passElectrical signatureLimiting timeOrders of magnitudeAmplification gainCochlear amplificationKHzΜsMembrane protein prestinVoltageKineticsCapacitanceDamage resultsPhase correspondsElectrical
2017
Current carried by the Slc26 family member prestin does not flow through the transporter pathway
Bai JP, Moeini-Naghani I, Zhong S, Li FY, Bian S, Sigworth FJ, Santos-Sacchi J, Navaratnam D. Current carried by the Slc26 family member prestin does not flow through the transporter pathway. Scientific Reports 2017, 7: 46619. PMID: 28422190, PMCID: PMC5395958, DOI: 10.1038/srep46619.Peer-Reviewed Original ResearchNovel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing Loss via Regulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear
Tan WJ, Song L, Graham M, Schettino A, Navaratnam D, Yarbrough WG, Santos-Sacchi J, Ivanova AV. Novel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing Loss via Regulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear. Antioxidants & Redox Signaling 2017, 27: 489-509. PMID: 28135838, PMCID: PMC5564041, DOI: 10.1089/ars.2016.6851.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAnimalsAntioxidantsDisease Models, AnimalEar, InnerEvoked Potentials, Auditory, Brain StemGene Knockout TechniquesHearing LossHumansMiceMicroscopy, Electron, TransmissionMitochondriaOxidative StressProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseSignal TransductionSpiral GanglionTOR Serine-Threonine KinasesTumor Suppressor ProteinsConceptsAge-related hearing lossAuditory brainstem responseHearing lossKO miceEndocochlear potentialOxidative stressMitochondrial dysfunctionMitochondrial dysfunction/oxidative stressEnergy sensing pathwaysNovel therapeutic strategiesMolecular mechanismsPremature hearing lossCochlear stria vascularisMajor hearing lossChronic mitochondrial dysfunctionMetabolic etiologyWorldwide epidemicBrainstem responseClinical trialsVascular pathologyTherapeutic strategiesPathological alterationsABR parametersAO treatmentStria vascularis
2016
Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels
Lv C, Stewart WJ, Akanyeti O, Frederick C, Zhu J, Santos-Sacchi J, Sheets L, Liao JC, Zenisek D. Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels. Cell Reports 2016, 15: 2784-2795. PMID: 27292637, PMCID: PMC5334794, DOI: 10.1016/j.celrep.2016.05.045.Peer-Reviewed Original ResearchConceptsNeuromast hair cellsProper synaptic localizationHair cellsSynaptic ribbonsZebrafish genesProper localizationCalcium channelsSynaptic vesiclesSmall vesiclesEnhanced exocytosisFrameshift mutationRibeye proteinsSynaptic localizationVesiclesRelease sitesCellsRibeyeRibbon-like structuresNon-spiking cellsSensory systemsLocalizationGenesExocytosisSimilar numberProtein