Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. Glutamate is released by presynaptic neurons and signals primarily through postsynaptic ionotropic and metabotropic receptors. Excitatory amino acid transporters (EAATs) play critical roles in neuronal physiology and pathophysiology. In order for high frequency signaling to occur, neurotransmitter must be removed from the synapse soon after release. Additionally, low levels of ambient glutamate are required to prevent chronic excitotoxic activity of high-affinity receptors. In pathological circumstances, changes in glutamate transporter function and/or surface density can occur. Disruption of alkali ion gradients caused by metabolic impairment after stroke or traumatic brain injury cause transporter slowing or reversal, contributing to glutamate elevation and excitotoxicity. Bidirectional changes in transporter surface expression occur in both normal and pathophysiological conditions, causing ambient glutamate levels to change. Development of selective new ligands for modulating and imaging glutamate transporter density changes is an important goal. We propose to determine the first high-resolution atomic structure of a human neuronal glutamate transporter. This will provide new understanding of transporter function and facilitate development of selective and high- affinity EAAT ligands for potential therapeutic and diagnostic uses.

Public Health Relevance

In stroke, traumatic brain injury, ALS, and Alzheimer's diseases, levels of glutamate become too high, causing permanent loss of neurons. In the normal brain, glutamate levels are kept low by glutamate transporters, known as excitatory amino acid transporters (EAATs). This research will help explain how these proteins work and aid in the development of new drugs and imaging reagents that target them.

Agency
National Institute of Health (NIH)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM110690-01
Application #
8699001
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
City
Missoula
State
MT
Country
United States
Zip Code
59812