Hearing loss affects approximately 25 Million Americans. It also affects approximately 35% of those 65 and older. The primary cause of hearing loss in this group is a result of a loss of hair cells. Our interest is in understanding the molecular events that determine hair cell function, and how these events are controlled. We anticipate that such an understanding will allow rational therapies to be developed to treat hair cell loss. Hair cells are the primary transducers of sound serving to convert the mechanical energy of sound to a coded a neuronal one. In this proposal we are seeking to understand the molecular basis of the large conductance potassium channel as it affects hair cell function. Specifically, we are trying to elucidate the molecular determinants of how these channels bring about electrical tuning, a mechanism of frequency discrimination. We are also interested in determining the molecular basis of how they are clustered and co-localized with the voltage gated Ca channel at the basolateral surface of hair cells. The loss of the large conductance potassium channel in mice results in progressive hearing loss. We propose to extend previous work that has identified variations in the primary structure of the protein, and now seek to determine how interacting proteins influence its function. We have already isolated several proteins from the cochlea that interact with a limited portion of this channel using the yeast 2 hybrid technique. We will now determine how these interacting proteins affect the kinetic properties of this channel. We will also determine how these proteins affect it basolateral sorting, clustering and co-localization with voltage gated Ca channels. In addition, we will extend our successful yeast 2 hybrid approach to identify other proteins that interact with entire BK channel. These proteins too will be subject to similar assays. For these experiments we wilt use the chick as a model and will use a modular set of assays that we have developed to test their significance in affecting these physiological processes. ? ? ?

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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Donahue, Amy
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Yale University
Schools of Medicine
New Haven
United States
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Fleming, Matthew R; Brown, Maile R; Kronengold, Jack et al. (2016) Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell Rep 16:2281-8
Zhang, Yalan; Zhang, Xiao-Feng; Fleming, Matthew R et al. (2016) Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 165:434-448
Bai, Jun-Ping; Surguchev, Alexei; Joshi, Powrnima et al. (2012) CDK5 interacts with Slo and affects its surface expression and kinetics through direct phosphorylation. Am J Physiol Cell Physiol 302:C766-80
Surguchev, Alexei; Bai, Jun-Ping; Joshi, Powrnima et al. (2012) Hair cell BK channels interact with RACK1, and PKC increases its expression on the cell surface by indirect phosphorylation. Am J Physiol Cell Physiol 303:C143-50
Bai, Jun-Ping; Surguchev, Alexei; Navaratnam, Dhasakumar (2011) ýý4-subunit increases Slo responsiveness to physiological Ca2+ concentrations and together with ýý1 reduces surface expression of Slo in hair cells. Am J Physiol Cell Physiol 300:C435-46
Bian, Shumin; Bai, Jun-Ping; Chapin, Hannah et al. (2011) Interactions between ?-catenin and the HSlo potassium channel regulates HSlo surface expression. PLoS One 6:e28264
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
Bian, Shumin; Koo, Bon W; Kelleher, Stephen et al. (2010) A highly expressing Tet-inducible cell line recapitulates in situ developmental changes in prestin's Boltzmann characteristics and reveals early maturational events. Am J Physiol Cell Physiol 299:C828-35
Bai, Jun-Ping; Surguchev, Alexei; Ogando, Yudelca et al. (2010) Prestin surface expression and activity are augmented by interaction with MAP1S, a microtubule-associated protein. J Biol Chem 285:20834-43

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