Abstract

The function of a nerve terminal is to release transmitter molecules at the right time and the right place. Transmitter is stored inside synaptic vesicles in nerve terminals until vesicles fuse with the plasma membrane, releasing their contents. After release, new synaptic vesicles re-appear within seconds. Using cell-free reconstitution assays, the applicants have discovered that there are two pathways of synaptic vesicle formation. Naturally occurring mutants in mice lack one of these pathways, the one that utilizes the adaptor complex AP3. Such mice have major behavioral abnormalities, resembling aberrant behavior found in humans. This proposal aims at understanding the basic molecular mechanisms in the AP3 pathway, in order to understand the behavior and lay the basis for developing novel drug therapies. It also compares the two pathways of vesicle biogenesis, looking for differences in molecular mechanism, physiological relevance and development sequence.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS009878-30
Application #
6186700
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Chiu, Arlene Y
Project Start
1978-09-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
30
Fiscal Year
2000
Total Cost
$282,931
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Jarousse, Nadine; Wilson, Joshua D; Arac, Demet et al. (2003) Endocytosis of synaptotagmin 1 is mediated by a novel, tryptophan-containing motif. Traffic 4:468-78
Dasgupta, Shoumita; Kelly, Regis B (2003) Internalization signals in synaptotagmin VII utilizing two independent pathways are masked by intramolecular inhibitions. J Cell Sci 116:1327-37
Blumstein, J; Faundez, V; Nakatsu, F et al. (2001) The neuronal form of adaptor protein-3 is required for synaptic vesicle formation from endosomes. J Neurosci 21:8034-42
de Wit, H; Lichtenstein, Y; Kelly, R B et al. (2001) Rab4 regulates formation of synaptic-like microvesicles from early endosomes in PC12 cells. Mol Biol Cell 12:3703-15
Jarousse, N; Kelly, R B (2001) The AP2 binding site of synaptotagmin 1 is not an internalization signal but a regulator of endocytosis. J Cell Biol 154:857-66
Jarousse, N; Kelly, R B (2001) Endocytotic mechanisms in synapses. Curr Opin Cell Biol 13:461-9
Qualmann, B; Kelly, R B (2000) Syndapin isoforms participate in receptor-mediated endocytosis and actin organization. J Cell Biol 148:1047-62
Faundez, V V; Kelly, R B (2000) The AP-3 complex required for endosomal synaptic vesicle biogenesis is associated with a casein kinase Ialpha-like isoform. Mol Biol Cell 11:2591-604
Qualmann, B; Kessels, M M; Kelly, R B (2000) Molecular links between endocytosis and the actin cytoskeleton. J Cell Biol 150:F111-6
Marullo, S; Faundez, V; Kelly, R B (1999) Beta 2-adrenergic receptor endocytic pathway is controlled by a saturable mechanism distinct from that of transferrin receptor. Receptors Channels 6:255-69

Showing the most recent 10 out of 43 publications