Abstract

The proposal seeks to bring a molecular understanding of how large conductance calcium activated potassium (BK) channels, which are important for hearing affect hair cell function using mouse and chicken hair cells as a model system. The channels consist of the Slo protein and a variable number of associated proteins The proposal seeks to determine how BK channels are localized at the basolateral surface of hair cells. In particular the proposal seeks to ascertain how Slo trafficking in hair cells occur ad tests the hypothesis that Slo in hair cells uses the basolateral secretory pathway in polarized epithelial cells. The role of phosphorylation and associated proteins in bringing about basolateral sorting will be explored. The project will also determine how splicing, phosphorylation and Slo associated proteins affect BK kinetics attempting to relate these changes to those in native hair cells.

Public Health Relevance

The proposal seeks to bring a molecular understanding of the role large conductance calcium activated potassium (BK) channels play in hair cell function. These channels have been shown to be crucial for setting a hair cells receptor potential allowing these cells to respond to sustained bundle displacements with graded receptor potentials. The channels consist of the Slo protein and a variable number of associated proteins. Using mouse and chicken hair cells as a model system, we hope to understand the molecular basis of its localization to the base of hair cells. The project will also determine how splicing, phosphorylation and Slo associated proteins affect BK kinetics attempting to relate these changes to those in chicken hair cells, where these properties change along the tonotopic axis. As such the chick epithelium is a well defined crucible that will help bring about an understanding of BK channel function, which is important not only for the understanding of hair cell physiology, but also for understanding myriad other diseases such as hypertension and epilepsy in which BK kinetics play a critical role.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC007894-06A1
Application #
8448046
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2006-06-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$353,370
Indirect Cost
$140,870

  Institution

Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

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
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; 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
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
Bai, Jun-Ping; Surguchev, Alexei; Bian, Shumin et al. (2010) Combinatorial cysteine mutagenesis reveals a critical intramonomer role for cysteines in prestin voltage sensing. Biophys J 99:85-94
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

Showing the most recent 10 out of 13 publications