With the identification of prestin, an anion transporter (SLC26) family member, as the elusive lateral membrane motor protein of the outer hair cell (OHC), we are faced with the possibility of understanding how this single molecule can effect the mammal?s exquisite sense of hearing. We propose to target a focused set of aims, including 1) determining the role of a leakage conductance in prestin, distinct from its transporter pathway, in hearing and defining its structural basis; 2) determine the role of anion binding residues, and the influence of mechanical load in governing prestin?s frequency dependence; simultaneous measures of sensor charge movement (NLC), electromotility and evoked-forces are planned and 3) determine the structural components of pillars that link prestin to the underlying cytoskeleton, and confirming the importance of such links in hearing. In order to reach these goals, we will employ a host of genetic, electrophysiological, molecular biological and biochemical methods. We believe that the information that we obtain through these studies will aid in understanding how the OHC enables us to hear so well and in turn how we might combat pathologies of the OHC that afflict millions.
With the identification of prestin, an anion transport family member, as the elusive lateral membrane motor protein of the outer hair cell (OHC), we are faced with the possibility of understanding how this single molecule can effect the mammal?s exquisite sense of hearing. To that end, we will focus on defining the structural basis of a newly found leakage pathway in prestin that we believe plays a key role in Cl- conductance along the lateral wall. We will also determine what protein structures in prestin may give rise to the motor?s frequency dependence, focusing on the role of an identified anion binding site within it transport pathway and mechanical influences. In addition, we seek to identify the molecular links between, prestin and the underlying cytoskeleton; an important area that has largely been neglected. We believe that our molecular dissections will aid in understanding how the OHC enables us to hear so well and in turn how we might combat pathologies of the OHC that afflict millions.
|Santos-Sacchi, Joseph; Tan, Winston (2018) The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin. J Neurosci 38:5495-5506|
|Bai, Jun-Ping; Moeini-Naghani, Iman; Zhong, Sheng et al. (2017) Current carried by the Slc26 family member prestin does not flow through the transporter pathway. Sci Rep 7:46619|
|Tan, Winston J T; Song, Lei; Graham, Morven et al. (2017) 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. Antioxid Redox Signal 27:489-509|
|Lv, Caixia; Stewart, William J; Akanyeti, Otar et al. (2016) Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels. Cell Rep 15:2784-95|
|Santos-Sacchi, Joseph; Song, Lei (2016) Chloride Anions Regulate Kinetics but Not Voltage-Sensor Qmax of the Solute Carrier SLC26a5. Biophys J 110:2551-2561|
|McKay, Sharen E; Yan, Wayne; Nouws, Jessica et al. (2015) Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness. Am J Pathol 185:3132-40|
|Bian, Shumin; Navaratnam, Dhasakumar; Santos-Sacchi, Joseph (2013) Real time measures of prestin charge and fluorescence during plasma membrane trafficking reveal sub-tetrameric activity. PLoS One 8:e66078|
|Wu, T; Song, L; Shi, X et al. (2011) Effect of capsaicin on potassium conductance and electromotility of the guinea pig outer hair cell. Hear Res 272:117-24|
|Frucht, Corey S; Uduman, Mohamed; Kleinstein, Steven H et al. (2011) Gene expression gradients along the tonotopic axis of the chicken auditory epithelium. J Assoc Res Otolaryngol 12:423-35|
|Frucht, Corey S; Santos-Sacchi, Joseph; Navaratnam, Dhasakumar S (2011) MicroRNA181a plays a key role in hair cell regeneration in the avian auditory epithelium. Neurosci Lett 493:44-8|
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