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.
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