This project focuses on elucidating the molecular sites on vesicular neurotransmitter transporters that provide diversity and specificity for neurotransmitter uptake and targeting to sites of synaptic release. Recently, we showed that two proteins (VGLUT1 and VGLUT2) that transport glutamate into synaptic vesicles (SSVs) are selectively expressed on the SSVs in nerve terminals defining two classes of glutamatergic synapses in the CNS. We have now molecularly identified and functionally characterized a third isoform VGLUT3 and show that it is expressed in the varicosities and nerve terminals of a novel subset of excitatory neurons in the brain. The existence of pathway-specific, differential and complementary excitatory neurons in the central nervous system suggests that these three vesicular glutamate transporters may have distinct physiological roles in neurotransmission. Therefore, the overall goals for the next grant period are: 1) to define the differences in intrinsic functional activities of the three isoforms to better understand the mechanism of vesicular glutamate transport and 2) to identify the sites important for specific targeting to varicosities and axon terminals that might provide diversity in the functional capacity, sensitivity and plasticity of glutamatergic synapses. The results of these studies may provide the basis for future studies that can examine the differential role of specific sets of neurons in glutamate toxicity associated with seizure disorders and various neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036936-05A2
Application #
6776760
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
1998-01-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$318,663
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
He, Hongbo; Mahnke, Amanda H; Doyle, Sukhjeevan et al. (2012) Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning. J Neurosci 32:15886-901
Doyle, Sukhjeevan; Pyndiah, Slovénie; De Gois, Stéphanie et al. (2010) Excitation-transcription coupling via calcium/calmodulin-dependent protein kinase/ERK1/2 signaling mediates the coordinate induction of VGLUT2 and Narp triggered by a prolonged increase in glutamatergic synaptic activity. J Biol Chem 285:14366-76
Grewal, Sukhjeevan; Defamie, Norah; Zhang, Xiong et al. (2009) SNAT2 amino acid transporter is regulated by amino acids of the SLC6 gamma-aminobutyric acid transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission. J Biol Chem 284:11224-36
Mackenzie, Bryan; Illing, Anthony C; Morris, Marie E K et al. (2008) Analysis of a vesicular glutamate transporter (VGLUT2) supports a cell-leakage mode in addition to vesicular packaging. Neurochem Res 33:238-47
De Gois, Stephanie; Jeanclos, Elisabeth; Morris, Marie et al. (2006) Identification of endophilins 1 and 3 as selective binding partners for VGLUT1 and their co-localization in neocortical glutamatergic synapses: implications for vesicular glutamate transporter trafficking and excitatory vesicle formation. Cell Mol Neurobiol 26:679-93
Erickson, Jeffrey D; De Gois, Stephanie; Varoqui, Helene et al. (2006) Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size. Neurochem Int 48:643-9
Wilson, Nathan R; Kang, Jiansheng; Hueske, Emily V et al. (2005) Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J Neurosci 25:6221-34
De Gois, Stephanie; Schafer, Martin K-H; Defamie, Norah et al. (2005) Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits. J Neurosci 25:7121-33
Mackenzie, Bryan; Schafer, Martin K-H; Erickson, Jeffrey D et al. (2003) Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons. J Biol Chem 278:23720-30
Varoqui, Helene; Schafer, Martin K H; Zhu, Heming et al. (2002) Identification of the differentiation-associated Na+/PI transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J Neurosci 22:142-55

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