Neurons communicate by transmitting signals through highly specialized junctions called synapses. Frequent signaling through a synapse increases the strength of synaptic transmission; changes in the strength of synaptic transmission (also called synaptic plasticity) are believed to underlie learning and the development of complex behaviors. Several nonreceptor tyrosine kinases localize to synapses where they regulate synaptic transmission and plasticity. Since the Arg nonreceptor tyrosine kinase is localized to postsynaptic compartments of neurons, my proposed research will focus on characterizing the molecular interactions that Arg is involved in and whether these interactions lead to changes in synaptic transmission in response to presynaptic stimulus. These studies will lead to a better understanding of Abl family kinases function in neurons and how they affect synaptic transmission. The first step of the proposed research involves identifying substrates of Arg kinase activity by comparing tyrosine phosphorylation in wild-type vs. arg -/- mice and using functional phosphorylation assays in vivo and in vitro to confirm an enzyme-substrate interaction. As a second step, the effect of phosphorylation by Arg on the identified substrates function will be studied. Third, having identified substrates and its role upon phosphorylation, functional studies of the effect of Arg kinase activity will be assessed to establish its role in neurons. The ultimate goal of this work is to obtain valuable knowledge that can be applied in therapeutic procedures of patients that suffer of neurodegenerative disorders involving the loss of memory and/or the establishment of new memories and learning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS042365-03
Application #
6665238
Study Section
Special Emphasis Panel (ZRG1-BIOL-1 (01))
Program Officer
Stewart, Randall
Project Start
2002-09-01
Project End
Budget Start
2003-09-01
Budget End
2004-08-30
Support Year
3
Fiscal Year
2003
Total Cost
$38,576
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bradley, William D; Hernandez, Samuel E; Settleman, Jeffrey et al. (2006) Integrin signaling through Arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane. Mol Biol Cell 17:4827-36
Hernandez, Samuel E; Settleman, Jeffrey; Koleske, Anthony J (2004) Adhesion-dependent regulation of p190RhoGAP in the developing brain by the Abl-related gene tyrosine kinase. Curr Biol 14:691-6
Hernandez, Samuel E; Krishnaswami, Maithreyi; Miller, Ann L et al. (2004) How do Abl family kinases regulate cell shape and movement? Trends Cell Biol 14:36-44