Neurons in auditory brainstem pathways are capable of firing at very high rates with extraordinarily high temporal precision, allowing them to encode features of sound stimuli such as frequency, intensity and localization in space. Our ongoing research program in K+ channels over the past twenty years has cloned and identified many of the channels that determine the intrinsic electrical properties of neurons, and demonstrated that phosphorylation of such channels alters neuronal excitability. These channels include the Shaw-family Kv3.1b and Kv3.3 channels and the two-pore family TWIK channel, which are found at high levels in the presynaptic terminals of cochlear nucleus neurons and their postsynaptic targets, neurons of the medial nucleus of the trapezoid body. Evidence indicates that the intrinsic electrical properties of these neurons undergo rapid modification in response to changes in the auditory environment or to brief high frequency stimulation. We plan to determine the mechanism of these changes in excitability and to determine how they adapt the cell bodies and the presynaptic terminals to different frequencies of stimulation. The role of phosphorylation/dephosphorylation of the potassium channel subunits will be assessed using phospho-specific antibodies for immunocytochemistry and by direct electrophysiological measurements in mice in which one or more of the subunits have been deleted by homologous recombination. We will also test the hypothesis that the leakage potassium current in these neurons, which determines the membrane time constant, and therefore plays a central role in accuracy of timing, is regulated by changes in the sumoylation or phosphorylation state of the TWIK channel. An understanding of how rapid changes in the function of ion channels adapt the nervous system to different sensory environments may lead to therapies for a variety of hearing disorders including tinnitus, age-related hearing loss and audiogenic seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001919-18
Application #
7788145
Study Section
Biophysics of Synapses, Channels, and Transporters Study Section (BSCT)
Program Officer
Cyr, Janet
Project Start
1993-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$329,645
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gribkoff, Valentin K; Kaczmarek, Leonard K (2017) The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology 120:11-19
Kaczmarek, Leonard K; Aldrich, Richard W; Chandy, K George et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels. Pharmacol Rev 69:1-11
Kaczmarek, Leonard K; Zhang, Yalan (2017) Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance. Physiol Rev 97:1431-1468
Chambers, Anna R; Pilati, Nadia; Balaram, Pooja et al. (2017) Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage. Sci Rep 7:17496
Khare, Swati; Nick, Jerelyn A; Zhang, Yalan et al. (2017) A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLoS One 12:e0173565
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
Brown, Maile R; El-Hassar, Lynda; Zhang, Yalan et al. (2016) Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons. J Neurophysiol 116:106-21
Onorati, Marco; Li, Zhen; Liu, Fuchen et al. (2016) Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep 16:2576-2592
Zhang, Yalan; Kaczmarek, Leonard K (2016) Kv3.3 potassium channels and spinocerebellar ataxia. J Physiol 594:4677-84
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

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