The purpose of the studies proposed in this grant is to understand, in molecular terms, the mechanisms underlying the localization of ion channels to specific subcellular regions in neurons. Studies will concentrate on elucidating the mechanisms by which the voltage-gated K+ channels from the Kv4 and Kv1 families are localized to and within subcellular compartments in neurons.
The aims are as follows: 1. To investigate the mechanisms underlying dendritic localization of Kv1.3 in Purkinje cells of the cerebellum. 2. To define the role of adaptor proteins in the transport and regulation of expression of Kv4.2. 3. To use phage display antibodies to investigate the mechanisms underlying localization of Kv4.2 within the dendritic compartment of cortical and hippocampal pyramidal cells. 4. To identify proteins that interact with the dileucine motif of Kv4.2 and play a role in mediating dendritic targeting of the channel. The ultimate goal of this research is to understand how K+ channels are localized to specific subcellular regions in neurons. This is an important aspect of K+ channel regulation, derangements of which have been shown to lead to diseases such as epilepsy. K+ channel localization will also serve as a model to understand subcellular trafficking of proteins in general. Subcellular trafficking of proteins underlies many essential functions of neurons, such as learning and memory. In addition faulty protein trafficking has been linked to such neurological diseases as Alzheimer's disease and Huntington's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS041963-04A2
Application #
7145365
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Silberberg, Shai D
Project Start
2001-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$293,400
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Balasanyan, Varuzhan; Watanabe, Kaori; Dempsey, William P et al. (2017) Structure and Function of an Actin-Based Filter in the Proximal Axon. Cell Rep 21:2696-2705
Arnold, Don B; Gallo, Gianluca (2014) Structure meets function: actin filaments and myosin motors in the axon. J Neurochem 129:213-220
Mora, Rudy J; Roberts, Richard W; Arnold, Don B (2013) Recombinant probes reveal dynamic localization of CaMKII? within somata of cortical neurons. J Neurosci 33:14579-90
Watanabe, Kaori; Al-Bassam, Sarmad; Miyazaki, Yusuke et al. (2012) Networks of polarized actin filaments in the axon initial segment provide a mechanism for sorting axonal and dendritic proteins. Cell Rep 2:1546-53
Al-Bassam, Sarmad; Xu, Min; Wandless, Thomas J et al. (2012) Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. Cell Rep 2:89-100
Lewis Jr, Tommy L; Mao, Tianyi; Arnold, Don B (2011) A role for myosin VI in the localization of axonal proteins. PLoS Biol 9:e1001021
Lewis Jr, Tommy L; Mao, Tianyi; Svoboda, Karel et al. (2009) Myosin-dependent targeting of transmembrane proteins to neuronal dendrites. Nat Neurosci 12:568-76
Arnold, Don B (2009) Actin and microtubule-based cytoskeletal cues direct polarized targeting of proteins in neurons. Sci Signal 2:pe49
Arnold, Don B (2007) Polarized targeting of ion channels in neurons. Pflugers Arch 453:763-9
Rivera, Jacqueline; Chu, Po-Ju; Lewis Jr, Tommy L et al. (2007) The role of Kif5B in axonal localization of Kv1 K(+) channels. Eur J Neurosci 25:136-46

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