Functional Properties of Hair Cells and Spiral Ganglion Neurons

Summary

Principal Investigator: Ebenezer N Yamoah
Abstract: DESCRIPTION (provided by applicant): Voltage-gated Ca2+ channels and Ca2+ regulate the electrical and biochemical properties of hair cells (HCs) and spiral ganglia neurons (SGNs). However, the cellular mechanisms of the Ca2+-mediated functions remain unclear. The overall goal of this proposal is to deploy innovative molecular biological, electrophysiological, and imaging techniques, many inspired from previous Ca2+ channel studies, for the discovery of fundamental and newly accessible arenas of Ca2+ channel and Ca2+-mediated physiology in HCs and SGNs. This proposal drives three aims that address various aspects of HC and SGN Ca2+ channel physiology, each with fundamental and therapeutic implications. The overall hypothesis is that multiple Ca2+ channels in HCs and SGNs regulate distinct functions, ranging from short-term membrane excitability to long-term developmental processes and gene expression. For example, we predict that the Cav1.2 channel is expressed in SGNs, serving both as a channel and as a transcription factor. The Aims are: (1) To unequivocally resolve the distinct properties and functions of the subtypes of Ca2+ channels in HCs and SGNs. The identity and functions of the Ca2+ channels other than the Cav1.3 subtype remain uncertain, despite large potential physiological ramifications. We have identified 7 distinct spliced variants of Cav3.1 and predict that alternative splicing of mRNA produces distinct functional Cav3.1, which are specific to HCs. Additionally, we have strong evidence to suggest that SGNs deploy several other non-Cav1.3 channels to promote distinct functions. (2) To continue to define the role of Ca2+ entry through distinct channels in regulating local and global Ca2+ domains in HCs and SGNs. (3) To identify the distinct Ca2+ channel subtype/s that serve as transcriptional factors in SGNs. We predict SGNs express conventional and unconventional neuronal Ca2+ channels, including the 11C-cardiac Ca2+ channel (Cav1.2). We hypothesize that under normal conditions, the Cav1.2 channels serve mainly as a transcriptional factor in SGNs, bridging the gap between the plasma membrane and the nucleus. The role of Ca2+-mediated activation of other physiologically important transcriptional factors such as CREB will be delineated. The project will be conducted using mice, and physiological and biochemical tools. Overall, this proposal will answer fundamental unknowns of Ca2+-mediated electrical and biochemical changes in HC and SGN physiology. Hair cells (HCs) in the inner ear convert sound and balance signals into electrical impulses, which are then transmitted to spiral ganglia neurons (SGNs) with remarkable precision and sensitivity. Our long-term goal is to understand how Ca2+ channel proteins and Ca2+ ions regulate the electrical activity and biochemistry of HCs and SGNs. Studies from our group and others have demonstrated that Ca2+-mediated changes underlie electrical activity of HCs and SGNs and indeed, Ca2+ may turn on genes that are responsible for neuronal survival. We know very little about the different Ca2+ channels that confer Ca2+-dependent changes in HCs and SGNs, despite their potential therapeutic ramifications. Strong evidence from data in developmental cell biology and electrophysiology motivates our overall hypothesis that multiple Ca2+ channels in HCs and SGNs regulate distinct functions ranging from short-term membrane excitability to long-term developmental processes and gene expression. For example, we predict that the channel Cav1.2 is expressed in SGNs, serving as a channel as well as a transcription factor. These studies should reveal how HCs and SGNs coordinate and regulate their electrical and biochemical machinery, information that might be exploited to induce HC and SGN survival after damage.
Funding Period: 2000-01-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Conservation of hearing by simultaneous mutation of Na,K-ATPase and NKCC1
    Rodney C Diaz
    Department of Otolaryngology Head and Neck Surgery, University of California Davis School of Medicine, 1515 Newton Court, Davis, CA 95618, USA
    J Assoc Res Otolaryngol 8:422-34. 2007
  2. pmc The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+)-dependence of a transient K+ current
    Snezana Levic
    Program in Communication Science, Department of Anesthesiology and Pain Medicine, School of Medicine, University of California Davis, Davis, California, USA
    PLoS ONE 6:e29005. 2011
  3. pmc Plasticity in membrane cholesterol contributes toward electrical maturation of hearing
    Snezana Levic
    Department of Anesthesiology and Pain Medicine, Program in Communication Science, University of California Davis School of Medicine, Davis, California 95618, USA
    J Biol Chem 286:5768-73. 2011
  4. pmc Release and elementary mechanisms of nitric oxide in hair cells
    Ping Lv
    Center for Neuroscience, Department of Anesthesiology and Pain Medicine, Program in Communication Sciences, University of California, Davis, Davis, CA 95616, USA
    J Neurophysiol 103:2494-505. 2010
  5. pmc Regeneration of the mammalian inner ear sensory epithelium
    Dongguang Wei
    Center for Neuroscience, Program in Communication Science, Department of Anesthesiology and Pain Medicine, University of California, Davis, California 95618, USA
    Curr Opin Otolaryngol Head Neck Surg 17:373-80. 2009
  6. pmc Identification of transcription factor-DNA interactions using chromatin immunoprecipitation assays
    Liping Nie
    Department of Otolaryngology, Center for Neuroscience, University of California, Davis CA, USA
    Methods Mol Biol 493:311-21. 2009
  7. pmc Synthesis of biotin-labeled RNA for gene expression measurements using oligonucleotide arrays
    Ana E Vazquez
    Department of Otolaryngology, Center for Neuroscience University of California, Davis, CA, USA
    Methods Mol Biol 493:21-9. 2009
  8. pmc Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear
    Liping Nie
    Center for Neuroscience, Program in Communication Science, University of California, Davis, 1544 Newton Ct, Davis, CA 95618, USA
    J Neurophysiol 100:2287-99. 2008
  9. pmc Otoconin-90 deletion leads to imbalance but normal hearing: a comparison with other otoconia mutants
    X Zhao
    Genetics Department, Boys Town National Research Hospital, 555 North 30th Street, Omaha, NE 68131, USA
    Neuroscience 153:289-99. 2008
  10. pmc Development and regeneration of hair cells share common functional features
    Snezana Levic
    Department of Otolaryngology, Program in Communication Science, Center for Neuroscience, University of California, 1544 Newton Court, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 104:19108-13. 2007

Research Grants

Detail Information

Publications11

  1. pmc Conservation of hearing by simultaneous mutation of Na,K-ATPase and NKCC1
    Rodney C Diaz
    Department of Otolaryngology Head and Neck Surgery, University of California Davis School of Medicine, 1515 Newton Court, Davis, CA 95618, USA
    J Assoc Res Otolaryngol 8:422-34. 2007
    ..These observations provide insight into the detailed mechanisms of EP generation, and results of combination-knockout experiments may have important implications in the future treatment of drug-induced and age-related hearing losses...
  2. pmc The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+)-dependence of a transient K+ current
    Snezana Levic
    Program in Communication Science, Department of Anesthesiology and Pain Medicine, School of Medicine, University of California Davis, Davis, California, USA
    PLoS ONE 6:e29005. 2011
    ....
  3. pmc Plasticity in membrane cholesterol contributes toward electrical maturation of hearing
    Snezana Levic
    Department of Anesthesiology and Pain Medicine, Program in Communication Science, University of California Davis School of Medicine, Davis, California 95618, USA
    J Biol Chem 286:5768-73. 2011
    ..Collectively, these findings provide evidence that developmental plasticity of lipid microdomains and the ensuing changes in K(+) currents are important determinants of one of the hallmarks in the maturation of hearing...
  4. pmc Release and elementary mechanisms of nitric oxide in hair cells
    Ping Lv
    Center for Neuroscience, Department of Anesthesiology and Pain Medicine, Program in Communication Sciences, University of California, Davis, Davis, CA 95616, USA
    J Neurophysiol 103:2494-505. 2010
    ..Finally, NO increases the magnitude of Ca(2+)-activated K(+) currents via direct NO nitrosylation. We conclude that NO-mediated inhibition serves as a component of efferent nerve modulation of hair cells...
  5. pmc Regeneration of the mammalian inner ear sensory epithelium
    Dongguang Wei
    Center for Neuroscience, Program in Communication Science, Department of Anesthesiology and Pain Medicine, University of California, Davis, California 95618, USA
    Curr Opin Otolaryngol Head Neck Surg 17:373-80. 2009
    ..This review will focus on 'self-repair' of the mammalian inner ear sensory epithelium, including recruiting the in-situ proliferation and differentiation of endogenous cells at the damaged site and the autologous transplantation..
  6. pmc Identification of transcription factor-DNA interactions using chromatin immunoprecipitation assays
    Liping Nie
    Department of Otolaryngology, Center for Neuroscience, University of California, Davis CA, USA
    Methods Mol Biol 493:311-21. 2009
    ....
  7. pmc Synthesis of biotin-labeled RNA for gene expression measurements using oligonucleotide arrays
    Ana E Vazquez
    Department of Otolaryngology, Center for Neuroscience University of California, Davis, CA, USA
    Methods Mol Biol 493:21-9. 2009
    ..Either one of these techniques will identify the specific cell types that express the genes of interests...
  8. pmc Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear
    Liping Nie
    Center for Neuroscience, Program in Communication Science, University of California, Davis, 1544 Newton Ct, Davis, CA 95618, USA
    J Neurophysiol 100:2287-99. 2008
    ..The differential expression of the channel during development and the pharmacology of the inner ear Cav3.1 channel may have contributed to the difficulties associated with identification of the non-Cav1.3 currents...
  9. pmc Otoconin-90 deletion leads to imbalance but normal hearing: a comparison with other otoconia mutants
    X Zhao
    Genetics Department, Boys Town National Research Hospital, 555 North 30th Street, Omaha, NE 68131, USA
    Neuroscience 153:289-99. 2008
    ..Furthermore, the combination of direct electrophysiological measures and a series of behavioral tests can be used to interpret the imbalance severity arising from altered inputs from the gravity receptor end organ...
  10. pmc Development and regeneration of hair cells share common functional features
    Snezana Levic
    Department of Otolaryngology, Program in Communication Science, Center for Neuroscience, University of California, 1544 Newton Court, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 104:19108-13. 2007
    ..Remarkably, this process is recapitulated during hair-cell regeneration, suggesting that the transient expression of Ca(v)3.1 and the ensuing SAPs are signatures of hair cell development and regeneration...
  11. pmc Posthearing Ca(2+) currents and their roles in shaping the different modes of firing of spiral ganglion neurons
    Ping Lv
    The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China 050017
    J Neurosci 32:16314-30. 2012
    ..Additionally, there were differential expressions of distinct Ca(2+) current densities in the apicobasal contour of the adult cochlea. This report provides invaluable insights into Ca(2+)-dependent processes in adult SGNs...

Research Grants30

  1. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  2. IDENTIFICATION OF ACOUSTICO-LATERALIS TRANSMITTERS
    Dennis G Drescher; Fiscal Year: 2013
    ....
  3. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  4. Synaptic Determinants of Vestibular Afferent Dynamics
    Richard D Rabbitt; Fiscal Year: 2013
    ..Results from these investigations are expected to support the development of targeted therapies for peripheral vestibular disorders such as Mnire's syndrome and benign paroxysmal positional vertigo. ..
  5. Roles of K channels in spiral ganglia neurons in health, diseases and aging.
    Ebenezer N Yamoah; Fiscal Year: 2013
    ..Our ultimate goal is to design drugs that may help alleviate/prevent neuronal death in our aging population and in several diseases affecting the inner ear. ..