The goal of this research is to further elucidate the physiological properties of chemical synapses between nerve cells. In particular, this project considers the ability of calcium (Ca) ions to trigger neurotransmitter secretion from presynaptic nerve terminals. Experiments will be performed upon squid """"""""giant"""""""" presynaptic terminals, one of the few nerve terminals large enough to permit direct measurement and manipulation of presynaptic function. This project employs two complementary strategies to attempt to elucidate the molecular basis for Ca-dependent secretion of neurotransmitters. First, evaluation of the physiological properties of transmissions will yield physiological constraints useful in determining the validity of various molecular models for transmitters secretion. Specifically, the spatial extent of presynaptic Ca action, the quantitative relationship between presynaptic Ca concentration and release rates, and detailed study of the time course, or kinetics, of release will be considered. Second, the role of specific molecules though to be important in Ca-dependent transmitter secretion will be evaluated by employing microinjection methods to ask whether molecular probes known to perturb these molecules have the predicated effects upon transmitter secretion. The specific molecules to be considered are: calmodulin, protein kinases, such as a Ca/calmodulin- dependent protein kinase and protein kinase C, inositol triphosphate, and GTP-binding proteins. Elucidation of the general question of the molecular basis of transmitter secretion, as well as the more specific questions of the role of various molecules in presynaptic function, will help define the physiological processes underlying synpatic transmission and may ultimately clarify the action of numerous neurological disorders that result from abnormal synaptic function.
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| Hilfiker, Sabine; Benfenati, Fabio; Doussau, Frederic et al. (2005) Structural domains involved in the regulation of transmitter release by synapsins. J Neurosci 25:2658-69 |
| Nishiki, Tei-ichi; Augustine, George J (2004) Dual roles of the C2B domain of synaptotagmin I in synchronizing Ca2+-dependent neurotransmitter release. J Neurosci 24:8542-50 |
| Nishiki, Tei-ichi; Augustine, George J (2004) Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. J Neurosci 24:6127-32 |
| Augustine, George J; Santamaria, Fidel; Tanaka, Keiko (2003) Local calcium signaling in neurons. Neuron 40:331-46 |
| Morgan, Jennifer R; Prasad, Kondury; Jin, Suping et al. (2003) Eps15 homology domain-NPF motif interactions regulate clathrin coat assembly during synaptic vesicle recycling. J Biol Chem 278:33583-92 |
| Xu, Jianhua; Xu, Yimei; Ellis-Davies, Graham C R et al. (2002) Differential regulation of exocytosis by alpha- and beta-SNAPs. J Neurosci 22:53-61 |
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