The purpose of the studies proposed in this grant is to understand the molecular mechanisms underlying polarized targeting of neuronal transmembrane proteins.
The specific aims of this grant will concentrate on three main levels of polarized targeting: 1. Targeting of proteins at the plasma membrane through compartment-specific endocytosis and vesicle docking. 2. Trafficking of vesicles containing either axonal or dendritic proteins to the appropriate polarized compartment. 3. Sorting of axonal and dendritic proteins into separate vesicles. The ultimate goal of this research is to understand how these targeting mechanisms produce surface distributions of proteins that are highly polarized. Relevance Protein targeting plays an important role in many physiological processes such as the establishment and maintenance of synaptic connections. In addition, defects in trafficking are associated with numerous neurological diseases of major clinical significance such as Alzheimer's and Huntington's disease.

Public Health Relevance

In neurons many transmembrane proteins are targeted specifically to either the axonal or dendritic compartment. The goal of this grant is to understand the molecular mechanisms that mediate this targeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041963-11
Application #
8490453
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (03))
Program Officer
Silberberg, Shai D
Project Start
2001-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$335,133
Indirect Cost
$128,261
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
Arnold, Don B; Gallo, Gianluca (2014) Structure meets function: actin filaments and myosin motors in the axon. J Neurochem 129:213-20
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
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
Chu, Po-Ju; Rivera, Jacqueline F; Arnold, Don B (2006) A role for Kif17 in transport of Kv4.2. J Biol Chem 281:365-73
Rivera, Jacqueline F; Chu, Po-Ju; Arnold, Don B (2005) The T1 domain of Kv1.3 mediates intracellular targeting to axons. Eur J Neurosci 22:1853-62
Rivera, Jacqueline F; Ahmad, Shoeb; Quick, Michael W et al. (2003) An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting. Nat Neurosci 6:243-50