Activity-Dependent Regulation of Prestin Expression in Mouse Outer Hair Cells
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Introduction to Sound and Hearing
Salamanca Study Abroad Program: Neurobiology of Hearing Cochlear mechanics R. Keith Duncan University of Michigan [email protected] Outline Passive and active cochlear mechanics Prestin and outer hair cell motility Tonotopicity A place code is a general principle of many sensory systems (somatotopic, retinotopic, others?) Damage (hair cell loss) at particular locations along the cochlea is correlated with hearing loss at a particular frequency. The place code in the cochlea is “tonotopic”, each sound frequency stimulating a particular location best. Cochlear place is “tuned” to particular frequencies. But how is this frequency “tuning” established? Era of the “traveling wave” begins 1 kHz Georg von Békésy (1899-1972) Awarded a Nobel prize in 1961 for studies on cochlear mechanics. See “Experiments in hearing” compiled by Glen Weaver. “in situ” measurements • Improve visualization with silver grains and strobe illumination • Measure amp. of motion for constant input pressure at various frequencies. Tonotopic Distribution of Frequency The cochlea is a frequency analyzer, breaking complex waves into frequency components. Tonos = tone; Topia = place Tonotopic = frequency place code 4 kHz 1 kHz 250 Hz Passive mechanics largely due to gradual changes in the stiffness of the basilar membrane. Base: thick and narrow Apex: thin and wide A (Nonlinear) Amplifier in the Ear Gain = Amplitude of basilar membrane Amplitude of stapes motion Use laser to measure membrane at one tonotopic position. Compare with stapes motion to get gain. Vary frequency of sound stimulus while keeping input (stapes motion) constant. Passive mechanics gives the “dead or high level shape” (like with Békésy). Something else happens at low sound levels in an alive animal (like with psychoacoustics). -
The Underwater Piano: a Resonance Theory of Cochlear Mechanics
The Underwater Piano: A Resonance Theory of Cochlear Mechanics by James Andrew Bell A thesis submitted for the degree of Doctor of Philosophy of The Australian National University July 2005 Visual Sciences Group Research School of Biological Sciences The Australian National University Canberra, ACT 0200 Australia This thesis is my original work and has not been submitted, in whole or in part, for a degree at this or any other university. Nor does it contain, to the best of my knowledge and belief, any material published or written by any other person, except as acknowledged in the text. In particular, I acknowledge the contribution of Professor Neville H. Fletcher who wrote Appendix A of Bell & Fletcher (2004) [§R 5.6 in this thesis] and who helped refine the text of that paper. Dr Ted Maddess provided the draft Matlab code used to perform the autocorrelation analysis reported in Chapter R7. Sharyn Wragg, RSBS Illustrator, drew some of the figures as noted. Signed: ……………………………………………… Date: ………………………………………………… Acknowledgements This thesis would not have appeared without the encouragement, support, and interest of many people. Yet, among them, the primary mainstay of this enterprise has been my wife, Libby, who has stayed by me on this long journey. I thank her for understanding and tolerance. Rachel, Sarah, Micah, Adam, Daniel, and Joshua have given their love and support, too, and that has been a source of strength. My supervisors have contributed in large measure, and I am grateful to all of them. Professor Anthony W. Gummer of the University of Tübingen saw the potential of this work at an early stage, and I thank him for his initiative in opening the door to this PhD study and providing some support (a grant from the German Research Council, SFB 430, to A.W. -
2.1 Drosophila Melanogaster
Overend, Gayle (2010) Drosophila as a model for the Anopheles Malpighian tubule. PhD thesis, University of Glasgow. http://theses.gla.ac.uk/1604/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Drosophila as a model for the Anopheles Malpighian tubule A thesis submitted for the degree of Doctor of Philosophy at the University of Glasgow Gayle Overend Integrative and Systems Biology Faculty of Biomedical and Life Sciences University of Glasgow Glasgow G11 6NU UK August 2009 2 The research reported within this thesis is my own work except where otherwise stated, and has not been submitted for any other degree. Gayle Overend 3 Abstract The insect Malpighian tubule is involved in osmoregulation, detoxification and immune function, physiological processes which are essential for insect development and survival. As the Malpighian tubules contain many ion channels and transporters, they could be an effective tissue for targeting with novel pesticides to control populations of Diptera. Many of the insecticide compounds used to control insect pest species are no longer suited to their task, and so new means of control must be found. -
Dopaminergic Loss of Cyclin-Dependent Kinase-Like 5 Recapitulates Methylphenidate-Remediable Hyperlocomotion in Mouse Model of CDKL5 Deficiency Disorder
Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder Downloaded from https://academic.oup.com/hmg/article-abstract/doi/10.1093/hmg/ddaa122/5863032 by University of Exeter user on 26 June 2020 Cian-Ling Jhang1, Hom-Yi Lee3,4, Jinchung Chen5, Wenlin Liao1,2 * 1 Institute of Neuroscience, 2 Research Center for Mind, Brain and Learning, National Cheng-Chi University, Taipei 116, Taiwan 3 Department of Psychology, 4 Department of Speech Language Pathology and Audiology, Chung Shan Medical University, Taichung 402, Taiwan 5 Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan UNCORRECTED MANUSCRIPT © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] page 1 Downloaded from https://academic.oup.com/hmg/article-abstract/doi/10.1093/hmg/ddaa122/5863032 by University of Exeter user on 26 June 2020 * To whom correspondence should be addressed: Wenlin Liao, PhD Associate Professor Institute of Neuroscience, National Cheng-Chi University 64, Sec. 2, Chi-Nan Road, Wen-Shan District Taipei 116, Taiwan Phone: 886-2-29393091 ext. 89621 UNCORRECTEDEmail: [email protected] MANUSCRIPT page 2 ABSTRACT Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in mammalian forebrain. Mutations in this gene Downloaded from https://academic.oup.com/hmg/article-abstract/doi/10.1093/hmg/ddaa122/5863032 by University of Exeter user on 26 June 2020 cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction and intellectual disability. -
The Hearing Gene Prestin Reunites Echolocating Bats
The hearing gene Prestin reunites echolocating bats Gang Li*, Jinhong Wang*, Stephen J. Rossiter†‡, Gareth Jones§, James A. Cotton†, and Shuyi Zhang*‡ *School of Life Science, East China Normal University, Shanghai 200062, China; †School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, United Kingdom; and §School of Biological Sciences, University of Bristol, Bristol BS8 1UG, United Kingdom Edited by Morris Goodman, Wayne State University School of Medicine, Detroit, MI, and approved July 10, 2008 (received for review March 4, 2008) The remarkable high-frequency sensitivity and selectivity of the Among all mammals, sensitivity to the highest frequencies occurs mammalian auditory system has been attributed to the evolution of in echolocating cetaceans and bats (17), which use sound for mechanical amplification, in which sound waves are amplified by orientation and often for the detection, localization, and classifi- outer hair cells in the cochlea. This process is driven by the recently cation of prey (18, 19). The processing of echolocation signals discovered protein prestin, encoded by the gene Prestin. Echolocating begins at the hair cells in the organ of Corti, continues along the bats use ultrasound for orientation and hunting and possess the auditory nerve, and terminates in the auditory cortex in the brain highest frequency hearing of all mammals. To test for the involve- (1). Prestin seems to be of major importance for hearing high ment of Prestin in the evolution of bat echolocation, we sequenced frequencies and for selective hearing, and both of these processes the coding region in echolocating and nonecholocating species. The are vital for echolocation. -
Comparative Molecular Dynamics Investigation of the Electromotile Hearing Protein Prestin
International Journal of Molecular Sciences Article Comparative Molecular Dynamics Investigation of the Electromotile Hearing Protein Prestin Gianfranco Abrusci 1,2,†, Thomas Tarenzi 1,3,†, Mattia Sturlese 4 , Gabriele Giachin 5 and Roberto Battistutta 5 and Gianluca Lattanzi 1,3,∗ 1 Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy; [email protected] (G.A.); [email protected] (T.T.) 2 Cineca, Via Magnanelli 6/3, Casalecchio di Reno, 40033 Bologna, Italy 3 TIFPA-INFN, Via Sommarive 14, 38123 Trento, Italy 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy; [email protected] 5 Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy; [email protected] (G.G.); [email protected] (R.B.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: The mammalian protein prestin is expressed in the lateral membrane wall of the cochlear hair outer cells and is responsible for the electromotile response of the basolateral membrane, following hyperpolarisation or depolarisation of the cells. Its impairment marks the onset of severe diseases, like non-syndromic deafness. Several studies have pointed out possible key roles of residues located in the Transmembrane Domain (TMD) that differentiate mammalian prestins as incomplete transporters from the other proteins belonging to the same solute-carrier (SLC) superfamily, which Citation: Abrusci, G.; Tarenzi, T.; are classified as complete transporters. Here, we exploit the homology of a prototypical incomplete Sturlese, M.; Giachin, G.; Battistutta, transporter (rat prestin, rPres) and a complete transporter (zebrafish prestin, zPres) with target R.; Lattanzi, G. -
A Role for Tectorial Membrane Mechanics in Activating the Cochlear Amplifer Amir Nankali1, Yi Wang4, Clark Elliott Strimbu4, Elizabeth S
www.nature.com/scientificreports OPEN A role for tectorial membrane mechanics in activating the cochlear amplifer Amir Nankali1, Yi Wang4, Clark Elliott Strimbu4, Elizabeth S. Olson3,4 & Karl Grosh1,2* The mechanical and electrical responses of the mammalian cochlea to acoustic stimuli are nonlinear and highly tuned in frequency. This is due to the electromechanical properties of cochlear outer hair cells (OHCs). At each location along the cochlear spiral, the OHCs mediate an active process in which the sensory tissue motion is enhanced at frequencies close to the most sensitive frequency (called the characteristic frequency, CF). Previous experimental results showed an approximate 0.3 cycle phase shift in the OHC-generated extracellular voltage relative the basilar membrane displacement, which was initiated at a frequency approximately one-half octave lower than the CF. Findings in the present paper reinforce that result. This shift is signifcant because it brings the phase of the OHC-derived electromotile force near to that of the basilar membrane velocity at frequencies above the shift, thereby enabling the transfer of electrical to mechanical power at the basilar membrane. In order to seek a candidate physical mechanism for this phenomenon, we used a comprehensive electromechanical mathematical model of the cochlear response to sound. The model predicts the phase shift in the extracellular voltage referenced to the basilar membrane at a frequency approximately one-half octave below CF, in accordance with the experimental data. In the model, this feature arises from a minimum in the radial impedance of the tectorial membrane and its limbal attachment. These experimental and theoretical results are consistent with the hypothesis that a tectorial membrane resonance introduces the correct phasing between mechanical and electrical responses for power generation, efectively turning on the cochlear amplifer. -
WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/090486 Al 16 June 2016 (16.06.2016) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 5/071 (2010.01) CI2N 5/073 (2010.01) kind of national protection available): AE, AG, AL, AM, C12N 11/02 (2006.01) C12Q 1/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/CA20 15/05 1297 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 9 December 2015 (09.12.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/089,5 12 9 December 2014 (09. 12.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: NATIONAL RESEARCH COUNCIL OF TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, CANADA [CA/CA]; M-55, 1200 Montreal Road, Ottawa, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Ontario K lA 0R6 (CA). -
Prestin Is the Motor Protein of Cochlear Outer Hair Cells
articles Prestin is the motor protein of cochlear outer hair cells Jing Zheng*, Weixing Shen*, David Z. Z. He*, Kevin B. Long², Laird D. Madison² & Peter Dallos* * Auditory Physiology Laboratory (The Hugh Knowles Center), Departments of Neurobiology and Physiology and Communciation Sciences and Disorders, Northwestern University, Evanston, Illinois 60208, USA ² Center for Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA ............................................................................................................................................................................................................................................................................ The outer and inner hair cells of the mammalian cochlea perform different functions. In response to changes in membrane potential, the cylindrical outer hair cell rapidly alters its length and stiffness. These mechanical changes, driven by putative molecular motors, are assumed to produce ampli®cation of vibrations in the cochlea that are transduced by inner hair cells. Here we have identi®ed an abundant complementary DNA from a gene, designated Prestin, which is speci®cally expressed in outer hair cells. Regions of the encoded protein show moderate sequence similarity to pendrin and related sulphate/anion transport proteins. Voltage-induced shape changes can be elicited in cultured human kidney cells that express prestin. The mechanical response of outer hair cells -
Cochlear Outer Hair Cell Motility
Physiol Rev 88: 173–210, 2008; doi:10.1152/physrev.00044.2006. Cochlear Outer Hair Cell Motility JONATHAN ASHMORE Department of Physiology and UCL Ear Institute, University College London, London, United Kingdom I. Introduction 174 II. Auditory Physiology and Cochlear Mechanics 174 A. The cochlea as a frequency analyzer 175 B. Cochlear bandwidths and models 175 C. Physics of cochlear amplification 177 D. Cellular origin of cochlear amplification 177 Downloaded from E. OHCs change length 178 F. Speed of OHC length changes 178 G. Strains and stresses of OHC motility 179 III. Cellular Mechanisms of Outer Hair Cell Motility 181 A. OHC motility is determined by membrane potential 182 B. OHC motility depends on the lateral plasma membrane 182 C. OHC motility as a piezoelectric phenomenon 183 physrev.physiology.org D. Charge movement and membrane capacitance in OHCs 184 E. Tension sensitivity of the membrane charge movement 185 F. Mathematical models of OHC motility 186 IV. Molecular Basis of Motility 186 A. The motor molecule as an area motor 186 B. Biophysical considerations 187 C. The candidate motor molecule: prestin (SLC26A5) 187 D. Prestin knockout mice and the cochlear amplifier 188 E. Genetics of prestin 188 on February 28, 2012 F. Prestin as an incomplete transporter 189 G. Structure of prestin 190 H. Function of the hydrophobic core of prestin 190 I. Function of the terminal ends of prestin 191 J. A model for prestin 191 V. Specialized Properties of the Outer Hair Cell Basolateral Membrane 192 A. Density of the motor protein 192 B. Cochlear development and the motor protein 193 C. -
Strand Breaks for P53 Exon 6 and 8 Among Different Time Course of Folate Depletion Or Repletion in the Rectosigmoid Mucosa
SUPPLEMENTAL FIGURE COLON p53 EXONIC STRAND BREAKS DURING FOLATE DEPLETION-REPLETION INTERVENTION Supplemental Figure Legend Strand breaks for p53 exon 6 and 8 among different time course of folate depletion or repletion in the rectosigmoid mucosa. The input of DNA was controlled by GAPDH. The data is shown as ΔCt after normalized to GAPDH. The higher ΔCt the more strand breaks. The P value is shown in the figure. SUPPLEMENT S1 Genes that were significantly UPREGULATED after folate intervention (by unadjusted paired t-test), list is sorted by P value Gene Symbol Nucleotide P VALUE Description OLFM4 NM_006418 0.0000 Homo sapiens differentially expressed in hematopoietic lineages (GW112) mRNA. FMR1NB NM_152578 0.0000 Homo sapiens hypothetical protein FLJ25736 (FLJ25736) mRNA. IFI6 NM_002038 0.0001 Homo sapiens interferon alpha-inducible protein (clone IFI-6-16) (G1P3) transcript variant 1 mRNA. Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 15 GALNTL5 NM_145292 0.0001 (GALNT15) mRNA. STIM2 NM_020860 0.0001 Homo sapiens stromal interaction molecule 2 (STIM2) mRNA. ZNF645 NM_152577 0.0002 Homo sapiens hypothetical protein FLJ25735 (FLJ25735) mRNA. ATP12A NM_001676 0.0002 Homo sapiens ATPase H+/K+ transporting nongastric alpha polypeptide (ATP12A) mRNA. U1SNRNPBP NM_007020 0.0003 Homo sapiens U1-snRNP binding protein homolog (U1SNRNPBP) transcript variant 1 mRNA. RNF125 NM_017831 0.0004 Homo sapiens ring finger protein 125 (RNF125) mRNA. FMNL1 NM_005892 0.0004 Homo sapiens formin-like (FMNL) mRNA. ISG15 NM_005101 0.0005 Homo sapiens interferon alpha-inducible protein (clone IFI-15K) (G1P2) mRNA. SLC6A14 NM_007231 0.0005 Homo sapiens solute carrier family 6 (neurotransmitter transporter) member 14 (SLC6A14) mRNA. -
The Cochlea: Mechanics and Transduction Jonathan Ashmore Neuroscience, Physiology and Pharmacology University College London
21/05/2015 Neurobiology of Hearing Salamanca, 20th May 2015 The cochlea: mechanics and transduction Jonathan Ashmore Neuroscience, Physiology and Pharmacology University College London [email protected] Not all tuning mechanisms use the same cellular design BM Hair cell frogs reptiles BM Hair birds cell Sound Soundinput Sound Soundinput BM Hair cell mammals 1 21/05/2015 In non-mammals, hair cells are electrically tuned: Neural tuning = intrinsic hair cell tuning Found in frog hair cells (Hudspeth et al); Turtle hair cells (Fettiplace et al.) In mammals, neural tuning = basilar membrane tuning Post-mortem 2 21/05/2015 The mammalian cochlea is a mechanical spectrum analyser B A Stapes Basilar membrane Fluid Fluid in motion at Round rest window BM stiffness high low Does the spiral contribute to cochlear performance? Only in a minor way. high frequencies low frequencies Sound enters from middle ear From Manoussaki et al., Phys Rev Letts E 2006 3 21/05/2015 Stapes Basilar membrane Fluid Fluid in motion at Round rest window d 2 x dx Simple m i h i k x f (t) , oscillator i dt 2 i dt i i i N 2 j i d xi dxi dxi dxi1 dxi1 Gi mi j 2 hi Ui (yi ) si 2 ki x Gi aS (t) j1 dt dt dt dt dt x = BM displacement ‘undamping’ y = tectorial membrane displacement 4 21/05/2015 What in silico models of the cochlea do: Inform intuition! Natural framework for functional genomics They indicate that there may be : Cochlear gradients of the mechanotransduction channel Cochlear gradients of K channel densities A small degree of longitudinal coupling along the cochlea From Robles & Ruggero, 2001 5 21/05/2015 Raw data from interferometry BM velocity normalised velocity (gain) i.e.