In cochlear inner hair cells (IHCs), Cav1.3 L-type voltage-gated Ca2+ channels mediate Ca2+ action potentials before the onset of hearing and Ca2+ signals that trigger exocytosis of neurotransmitter from IHCs onto auditory nerve afferents. These functions of Cav1.3 are crucial for the development and maintenance of hearing: mice lacking Cav1.3 are congenitally deaf, as are mice with upregulated Cav1.3 channels due to thyroid hormone deficiency. Thus, factors that regulate these channels can profoundly impact this first synapse in the auditory pathway. In this proposal, we will characterize two factors we have found to regulate Cav1.3 channels in IHCs: (1) CaBPs, which are a family of calmodulin-like Ca2+-binding proteins and (3) harmonin, a protein that corresponds to a genetic locus of Usher syndrome, a leading cause of combined deafness and blindness in humans. We propose that the macromolecular assembly of Cav1.3 with proteins such as harmonin and CaBPs dictates the strength and localization of Ca2+ signals in IHCs, and is crucial for the development and maintenance of auditory transmission. The goal of this proposal is to characterize the molecular mechanisms and functional consequences of these Cav1.3 interactions, and their physiological significance for hearing. Accomplishing this objective will clarify the modulatory influences of auditory Cav1.3 channels, which may be targeted pharmacologically in novel strategies to offset pathological changes involved in hereditary forms of deafness. 1 Project Narrative The proposed research will modulate voltage-gated Ca2+ channels in auditory hair cells. We will elucidate new structure/function relationships and modulatory mechanisms, which may be altered in hereditary forms of deafness.

Public Health Relevance

The proposed research will modulate voltage-gated Ca2+ channels in auditory hair cells. We will elucidate new structure/function relationships and modulatory mechanisms, which may be altered in hereditary forms of deafness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009433-06
Application #
8374115
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2008-12-15
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$347,995
Indirect Cost
$113,433
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Haeseleer, Françoise; Williams, Brittany; Lee, Amy (2016) Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina. J Biol Chem 291:15663-73
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Hardie, Jason; Lee, Amy (2016) Decalmodulation of Cav1 channels by CaBPs. Channels (Austin) 10:33-7
Krueger, Jamie N; Moore, Shannon J; Parent, Rachel et al. (2016) A novel mouse model of the aged brain: Over-expression of the L-type voltage-gated calcium channel CaV1.3. Behav Brain Res :
Stanika, Ruslan; Campiglio, Marta; Pinggera, Alexandra et al. (2016) Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology. Sci Rep 6:34528
Yang, Tian; Scholl, Elizabeth S; Pan, Ning et al. (2016) Expression and Localization of CaBP Ca2+ Binding Proteins in the Mouse Cochlea. PLoS One 11:e0147495
Lee, Amy; Wang, Shiyi; Williams, Brittany et al. (2015) Characterization of Cav1.4 complexes (α11.4, β2, and α2δ4) in HEK293T cells and in the retina. J Biol Chem 290:1505-21
Scharinger, Anja; Eckrich, Stephanie; Vandael, David H et al. (2015) Cell-type-specific tuning of Cav1.3 Ca(2+)-channels by a C-terminal automodulatory domain. Front Cell Neurosci 9:309
Joiner, Mei-Ling A; Lee, Amy (2015) Voltage-Gated Cav1 Channels in Disorders of Vision and Hearing. Curr Mol Pharmacol 8:143-8
Cao, Yan; Sarria, Ignacio; Fehlhaber, Katherine E et al. (2015) Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision. Neuron 87:1248-60

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