Objective
The synapse is the primary place at which information is transmitted from neuron to neuron or from neuron to target cell by means of presynaptically released neurotransmitters. One of the most important findings was the discovery that transmitter release is quantal in nature and is provided by synaptic vesicles. Docking of such vesicles to specialized sites along the presynaptic membrane, and fusion of docked vesicles with the plasma membrane results in the release of vesicular contents into the synaptic cleft.
Investigations during the last 30 years revealed several functionally important features of this mechanism
(1) Synaptic vesicles can be recycled, their membrane being recovered after fusion with the plasma membrane by endocytosis into endosomes, from which new synaptic vesicles are formed;
(2) The release of synaptic vesicles displays plasticity depending on the clustering of vesicles in the presynaptic terminal and on the formation of readily releasable and more distant pools of vesicles;
(3) The behaviour of synaptic vesicles is highly dependent on the presence of a wide range of presynaptic proteins which are crucial for the whole life-cycle of the vesicles including transmitter uptake, vesicle attachment and membrane trafficking (docking, fusion exocytosis, endocytosis and recycling) as well as for their dependence on modulatory molecules.
Despite extensive studies carried out in numerous laboratories, many aspects of this extremely complicated mechanism still remain unclear. The main goal of the project is the characterization of trafficking mechanisms for different types of vesicles in cells, their connection with specific synaptic proteins and their dependence on the characteristics of signals triggering exocytosis under normal and pathologic conditions. The proposed projects are designed to include two main functional systems, representing exocytosis in either nerve terminals of hippocampal neurones or neuroendocrine (chromaffin and PC12) cells, which use the two major types of secretory vesicles - large dense core vesicles (LDCV), which contain mainly peptides, and small synaptic-like vesicles (SSV), respectively. This will allow discrimination of the common and specific features of regulated exocytosis for different types of vesicles and will provide clues on the specificity of synaptic proteins.
The specific aims of the project are:
(1) to investigate kinetic characteristics of exocytosis of two types of secretory vesicles (synaptic and LDCV), its dependence on the type of stimulation;
(2) to determine the specificity of synaptic proteins implicated in vesicle recycling and exocytosis to indicated types of secretory vesicles, by measuring the protein distribution in chromaffin cells and hippocampal neuronal cultures;
(3) to examine the cross-talk between vesicular and synaptic protein trafficking, in terms of their colocalisation, during different types of stimulation;
(4) to examine the possibility and specificity of direct interaction of CAPS, Munc13 synaptic proteins and heterotrimeric G-proteins with isolated different types of vesicles by immunofluorescent and biochemical approaches;
(5) to study the influence of complexins, Munc13 and other proteins on the formation of SNARE complexes and SNARE disassembly;
(6) to determine possible coincidence of the changes in stimulus-induced vesicular and protein trafficking during pathologic conditions (hypoxia) which induce changes of secretory responses.
Each of the participating groups has appropriate methodology, skilled personnel and adequate equipment to reach the proposed tasks. All planned studies share a common theme and are complementary since every team will either concentrate on proteins involved in a definite step of regulated exocytosis or study the functional role of the same synaptic protein by different approaches. One of the most important outcomes of the proposed studies will be a precise knowledge about synaptic protein-mediated vesicular trafficking during exocytosis and, thereby, reveal crucial aspects of transmitter or hormone release, which in turn determines neuronal communication in brain activity as well as in endocrine regulation. Therefore, the proposed studies have the potential to contribute both to the fundamental knowledge of exocytosis or transmitter release and to lead to increased understanding of the mechanisms of numerous neurological and endocrine disorders that result from alterations of the intracellular trafficking mechanisms responsible for exocytosis. Understanding of these mechanisms will open the possibility to design new pharmacological tools.
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Coordinator
37077 Göttingen
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.