The pool of synaptic vesicles in a nerve terminal is only sufficient for a few seconds worth of intense synaptic activity. To allow synaptic activity to continue, a highly efficient mechanism for synaptic vesicle biogenesis in nerve terminals is triggered by synaptic vesicle exocytosis. At maximum capacity, the recycling machinery can keep up with prolonged release rates in the range of 5-10 Hz. Although several proteins are believed to contribute to the recycling mechanism only one, dynamin, has been identified genetically as a participant. Temperature sensitivity mutations in dynamin give rise to the shibire class of temperature-sensitive paralytics in Drosophila melanogaster. We will use the wild type and mutant dynamins in a search for proteins that interact with dynamin. We will explore, using biochemical and morphological techniques, what binds dynamin on to recycling membranes and what causes it to be released. To explore the function of the proteins we isolate, we examine their ability to regulate the binding of dynamin to membranes in vitro. We also express mutant forms of dynamin, defective in protein association, in transgenic flies, both wild type and carrying temperature-sensitive shibire allele. Because of the importance of vesicle recycling to synaptic function, long term presynaptic changes in synaptic efficiency could involve changes in the amounts or post- translational modification of dynamin and its associated proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015927-20
Application #
2891583
Study Section
Neurology C Study Section (NEUC)
Program Officer
Chiu, Arlene Y
Project Start
1979-12-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
20
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Marie, Bruno; Sweeney, Sean T; Poskanzer, Kira E et al. (2004) Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth. Neuron 43:207-19
Verstreken, Patrik; Koh, Tong-Wey; Schulze, Karen L et al. (2003) Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40:733-48
Jarousse, N; Kelly, R B (2001) Endocytotic mechanisms in synapses. Curr Opin Cell Biol 13:461-9
Roos, J; Hummel, T; Ng, N et al. (2000) Drosophila Futsch regulates synaptic microtubule organization and is necessary for synaptic growth. Neuron 26:371-82
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
Qualmann, B; Roos, J; DiGregorio, P J et al. (1999) Syndapin I, a synaptic dynamin-binding protein that associates with the neural Wiskott-Aldrich syndrome protein. Mol Biol Cell 10:501-13
Roos, J; Kelly, R B (1999) The endocytic machinery in nerve terminals surrounds sites of exocytosis. Curr Biol 9:1411-4

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