The broad long-term goal of this proposal is to define mechanisms involved in the regulation of information processing in the brain and how these mechanisms may impact on neuronal injury. Synaptic transmission, the major neuron specific mechanism for cell-to-cell communication, requires the concentration of neurotransmitters into synaptic vesicles to facilitate their rapid and precise release. Recently, the proteins responsible for the storage of the excitatory neurotransmitter glutamate in synaptic vesicles have been identified. However, the basic mechanisms by which these proteins (VGLUT1 and VGLUT2) function remain undetermined. Data suggests that VGLUT1 may also transport phosphate and function as a chloride channel. Since these additional functions will influence vesicular glutamate storage, it is important to clearly characterize the nature of the role that VGLUT1 plays in these processes.
Three Aims are proposed to address these issues.
The first Aim of this proposal is to define mechanism by which VGLUT1 catalyzes the accumulation of glutamate in synaptic vesicles.
The second Aim i s to determine if, in addition to transporting glutamate into vesicles, VGLUT1 also functions as a phosphate transport or chloride channel.
The third Aim i s to determine the secondary structure of VGLUT1 and the relationship of the structure to the functions of the protein. Progress in these Aims will lead to an improved understanding of the underlying molecular mechanisms of vesicular glutamate transport and insight into the role of VGLUT1 in vesicular storage of glutamate, synaptic transmission and excitotoxicity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research (K02)
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NST-2 Subcommittee (NST)
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Stewart, Randall
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Stanford University
Schools of Medicine
United States
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Tani, Hiroaki; Dulla, Chris G; Farzampour, Zoya et al. (2014) A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron 81:888-900
Morland, Cecilie; Nordengen, Kaja; Larsson, Max et al. (2013) Vesicular uptake and exocytosis of L-aspartate is independent of sialin. FASEB J 27:1264-74
Courville, Pascal; Quick, Matthias; Reimer, Richard J (2010) Structure-function studies of the SLC17 transporter sialin identify crucial residues and substrate-induced conformational changes. J Biol Chem 285:19316-23
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Dulla, Chris; Tani, Hiroaki; Okumoto, Sakiko et al. (2008) Imaging of glutamate in brain slices using FRET sensors. J Neurosci Methods 168:306-19
Myall, Nathaniel J; Wreden, Christopher C; Wlizla, Marcin et al. (2007) G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking. Mol Genet Metab 92:371-4
Tani, Hiroaki; Bandrowski, Anita E; Parada, Isabel et al. (2007) Modulation of epileptiform activity by glutamine and system A transport in a model of post-traumatic epilepsy. Neurobiol Dis 25:230-8
Wreden, Christopher C; Wlizla, Marcin; Reimer, Richard J (2005) Varied mechanisms underlie the free sialic acid storage disorders. J Biol Chem 280:1408-16

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