Our long-term goal is to understand how voltage-gated ion channels regulate hair cell excitability, influence sensory processing in the cochlea, and contribute to normal and abnormal auditory function. Calcium-sensitive potassium (BK) channels are widely distributed in neurons, muscle, and secretory cells. In neurons and sensory receptor cells, these channels constrain Ca2+ flux and influence Ca2+-triggered neurotransmission. In the cochlea, diminished BK channel function leads to profound auditory deficits. Therefore, the molecular mechanisms underlying proper channel function are of primary interest. The chicken cochlea provides a model system where we have shown that BK channel Ca2+ affinity and kinetics vary in a graded manner along the tonotopic axis. However, the mechanisms underlying this tonotopic variation, as well as the developmental acquisition and high Ca2+ sensitivity of hair cell BK currents, are poorly understood. Ion channel regulation is accomplished by a variety of means. In this proposal, we will explore BK regulation by alternative splicing (Aim 1), co-assembly with auxiliary (3 subunits (Aim 2), interaction with synaptic proteins (Aim 3), and trafficking to specific cellular microdomains (Aim 4). Quantitative molecular techniques, immunohistology, and electrophysiology will be used to identify the molecular determinants of hair cell BK channel behavior. These experiments will provide fundamental insight into the molecular physiology of auditory hair cells and may provide a window into the generation and maintenance of functional gradients along the cochlea. Errant ion channel function underlies numerous neurological disorders. Our proposal addresses the ways in which an important potassium channel variety (BK) is regulated in auditory sensory cells. This research provides the framework for understanding how changes in ion channel behavior affect normal and abnormal auditory function, leading to therapeutic strategies that target hair cell excitability through BK channel modulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007432-04
Application #
7534045
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2005-12-15
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
4
Fiscal Year
2009
Total Cost
$446,781
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Crumling, Mark A; Liu, Liqian; Thomas, Paul V et al. (2012) Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-?-cyclodextrin. PLoS One 7:e53280
Purcell, Erin K; Liu, Liqian; Thomas, Paul V et al. (2011) Cholesterol influences voltage-gated calcium channels and BK-type potassium channels in auditory hair cells. PLoS One 6:e26289
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