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. 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 #
5R01DC009433-04
Application #
7992366
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2008-12-15
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$305,465
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Zhu, Lu; Almaça, Joana; Dadi, Prasanna K et al. (2017) ?-arrestin-2 is an essential regulator of pancreatic ?-cell function under physiological and pathophysiological conditions. Nat Commun 8:14295
Wang, Xiaohan; Marks, Christian R; Perfitt, Tyler L et al. (2017) A novel mechanism for Ca2+/calmodulin-dependent protein kinase II targeting to L-type Ca2+ channels that initiates long-range signaling to the nucleus. J Biol Chem 292:17324-17336
Wang, Shiyi; Stanika, Ruslan I; Wang, Xiaohan et al. (2017) Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+ Channels at Excitatory Synapses. J Neurosci 37:4679-4691
Krueger, Jamie N; Moore, Shannon J; Parent, Rachel et al. (2017) A novel mouse model of the aged brain: Over-expression of the L-type voltage-gated calcium channel CaV1.3. Behav Brain Res 322:241-249
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
Hardie, Jason; Lee, Amy (2016) Decalmodulation of Cav1 channels by CaBPs. Channels (Austin) 10:33-7
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
Thomas, Jessica R; Lee, Amy (2016) Measuring Ca2+-Dependent Modulation of Voltage-Gated Ca2+ Channels in HEK-293T Cells. Cold Spring Harb Protoc 2016:pdb.prot087213
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
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

Showing the most recent 10 out of 35 publications