The long-term objectives are to understand how voltage-gated potassium (Kv) channels are localized into the proper subcellular compartments and how their localization affects neuronal excitability, and thus to develop new strategies for treating neurological diseases. Kv channel dysfunction causes diseases of brain, heart and muscle. Kv channels are the primary targets of pharmaceutical interventions to treat epilepsies, arrhythmias, neuropathic pain, and multiple sclerosis. Due to broad channel expression in many cell types, blockers or activators often bring severe side effects. Recent studies show that each Kv channel displays a distinct pattern of polarized targeting in neurons. It is the emerging theme that such polarized targeting affects neuronal excitability. However, the exact mechanism and function of Kv channel targeting remain mystery. Kv3 (Shaw) channels are unique among Kv channels in their high activation threshold and rapid deactivation kinetics. They are required for rapid spiking and involved in dendritic integration and transmitter release. Human adult-onset ataxia caused by mutations in Kv3.3 gene is a testament for their important functions. Reflecting their diverse functions, Kv3 channels display complex targeting patterns that are governed by unknown mechanisms. Our preliminary studies show that the two splice variants of Kv3.1 have identical channel properties but differentially regulate action potential firing. Interestingly, they differ in axon-dendrite targeting. Based on our preliminary data, we propose a new model that action potential firing is regulated by Kv3 channel targeting, which is in turn regulated by alternative splicing and protein phosphorylation. We will test three hypotheses in this model with three aims. By taking a multidisciplinary approach that includes electrophysiology, imaging, molecular biology and protein biochemistry techniques, we will determine whether:
(Aim 1) polarized targeting of Kv channels is critical for action potential firing;
(Aim 2) ankyrin G at the axon initial segment functions as a conditional barrier for Kv3 splice variants;
(Aim 3) protein phosphorylation regulates Kv3 channel targeting and hence action potential firing. Our research will contribute to generate a new therapeutic strategy and reveal new drug targets for specifically controlling Kv3 channel functions in neurons, e.g. developing small peptides and kinase inhibitors as the treatment of ataxia, epilepsy and sleeping disorders.

Public Health Relevance

Kv channels are the primary targets of pharmaceutical interventions to treat many diseases, in which the specificity of channel modulation is the key. Recent studies show that each Kv channel has its characteristic distribution pattern in nerve cells. Therefore, our project to understand how Kv channels are localized to regulate functions of nerve cells will contribute to generate novel strategies for treating diseases of the nervous systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062720-05
Application #
8423350
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2009-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$279,278
Indirect Cost
$93,093
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Jukkola, Peter; Gu, Chen (2015) Regulation of neurovascular coupling in autoimmunity to water and ion channels. Autoimmun Rev 14:258-67
Barry, Joshua; Gu, Yuanzheng; Jukkola, Peter et al. (2014) Ankyrin-G directly binds to kinesin-1 to transport voltage-gated Na+ channels into axons. Dev Cell 28:117-31
Gu, Yuanzheng; Gu, Chen (2014) Physiological and pathological functions of mechanosensitive ion channels. Mol Neurobiol 50:339-47
Barry, Joshua; Xu, Mingxuan; Gu, Yuanzheng et al. (2013) Activation of conventional kinesin motors in clusters by Shaw voltage-gated K+ channels. J Cell Sci 126:2027-41
Gu, Yuanzheng; Barry, Joshua; Gu, Chen (2013) Kv3 channel assembly, trafficking and activity are regulated by zinc through different binding sites. J Physiol 591:2491-507
Barry, Joshua; Gu, Chen (2013) Coupling mechanical forces to electrical signaling: molecular motors and the intracellular transport of ion channels. Neuroscientist 19:145-59
Gu, Yuanzheng; Barry, Joshua; McDougel, Robert et al. (2012) Alternative splicing regulates kv3.1 polarized targeting to adjust maximal spiking frequency. J Biol Chem 287:1755-69
Gu, Chen; Gu, Yuanzheng (2011) Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons. J Biol Chem 286:25835-47
Gu, Chen; Barry, Joshua (2011) Function and mechanism of axonal targeting of voltage-sensitive potassium channels. Prog Neurobiol 94:115-32
Barry, Joshua; Gu, Yuanzheng; Gu, Chen (2010) Polarized targeting of L1-CAM regulates axonal and dendritic bundling in vitro. Eur J Neurosci :

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