With the identification of prestin 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 have focused our interest on determining what protein structures may give rise to the motor's known biophysical attributes, including its temperature, tension, and voltage dependence. We hypothesize that these molecular activities arise and/or are influenced by interactions of prestin's intracellular C and N termini with other intracellular proteins and anions, and possibly by multimeric interactions, as well. We propose to target a focused set of aims, including 1) determine the contribution of prestin's C and N termini to prestin's signature biophysical attributes, and 2) develop a model hair cell system to study prestin expression, and targeting. In order to reach these goals, we will employ a host of 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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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Yale University
Schools of Medicine
New Haven
United States
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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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