Glutamate is the primary neurotransmitter in the brain, and is important for the majority of synaptic transmission and therefore learning and memory formation. At glutamatergic synapses, glutamate is released from the axon of the first neuron into the synaptic cleft, eventually activating glutamate receptors on the postsynaptic membrane of an adjacent neuron. A family of secondary active glutamate transporters localized to neuronal and glial membranes quickly import excess glutamate back into the cell, through coupling to electrochemical gradients of sodium ions, potassium ions, and protons. Mutations in these genes cause excitotoxicity and are associated with neurological disorders including Amyotrophic Lateral Sclerosis, Alzheimer's disease, stroke, and epilepsy; however, structural and mechanistic characterization of the ion specificity of mammalian transporters has proved to be challenging, ultimately hindering new strategies of pharmacological modulation. The majority of our understanding of this family arose from studies of conserved bacterial glutamate transporters, which generally couple transport to either exclusively sodium or protons. The proposed studies will use evolutionary analysis with structural biology to determine the molecular basis of ion specificity in glutamate transporters. We will accomplish this goal by pursuing two specific aims: (1) Characterize the evolutionary switch to a proton-coupled transporter; and (2) Determine the ion specificity of an ancestral glutamate transporter predating divergence of Na+ and proton-coupled transporters. Successful completion of these studies will increase understanding of how homologous transporters can harness different ionic gradients.

Public Health Relevance

Most cells require molecular machines called glutamate transporters to import extracellular glutamate. In the brain, these function to allow repeated rounds of signaling between neurons, while in bacteria these function in nutrient uptake. This proposal is to understand the molecular basis of how these proteins have adapted their functions as a response to changing environments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS102325-01
Application #
9328632
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Silberberg, Shai D
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065