PathwayStep2419 Glutamate Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Communication at the synapse involves the release of glutamate from the presynaptic neuron and its binding to glutamate receptors on the postsynaptic cell to generate a series of events that lead to propagation of the synaptic transmission. This process begins with the formation of synaptic vesicles in the presynaptic neuron, proceeds to the loading of glutamate into the vesicles, and concludes with the release of glutamate into the synaptic cleft. The glutamate life cycle in the neuron begins with the loading of the nascent synaptic vesicles with cytosolic glutamate with the help the transporter protein, VGLUT1, located in the synaptic vesicular membrane. Glutamate loaded vesicles are formed in the cytoplasm and then transported to a site close to the plasma membrane where the vesicle is docked with the help of several proteins. One of the key players in the docking process in Munc 18, which interacts with syntaxin (in the plasma membrane), MINT (Munc18 interacting molecule), and DOC2. These interactions along with the secondary interactions are needed for docking the synaptic vesicle to the plasma membrane. The docked synaptic vesicle is not ready for release until it undergoes molecular changes to prime it for fusion with the plasma membrane. Munc13 is one of the main players in the priming process. Munc 13 interacts with RIM (Rab3A interacting molecule) located in the synaptic vesicle. Munc 13 also interacts with DOC2. The precise molecular mechanisms of the interactions that result in docking versus priming are not clear and the docking and priming process have been combined in this annotation of this pathway. Once primed the synaptic vesicle is ready for release. Synaptic transmission involves an action potential that is generated in the presynaptic cell which induces the opening of voltage gated Ca2+ channels (VGCC) located in the plasma membrane of the presynaptic neuron. Typically N, P/Q and R type of VGCCs are involved in the neurotransmitter release. Ca2+ influx through these channels results in the rise of intracellular Ca2+ concentration. In the microdomain of glutamatergic synapses, the Ca2+ concentration could rise between 10-25 micro molar. Synaptotagmin, a Ca2+-binding protein located in the synaptic vesicular membrane, responds to the rise in the Ca2+ levels in the microdomain and induces a synaptic vesicle membrane curvature that favors vesicle fusion. Fusion of the synaptic vesicle with the plasma membrane is characterized by the formation of a trimeric trans-SNARE complex that involves VAMP2 from the synaptic vesicle membrane, and syntaxin and SNAP-25 from plasma membrane. Vesicle fusion incorporates the synaptic vesicle membrane into the plasma membrane, releasing the vesicle contents (glutamate) into the synaptic cleft. Postfusion the synaptic vesicle membrane proteins (VAMP2, Rab3A, VGLUT1, and synaptotagmin) are also found in the plasma membrane. Edited: Mahajan, SS, 2008-01-14 16:06:22 GENE ONTOLOGYGO:0014047 Pubmed10440375 Pubmed11001057 Pubmed16704978 Pubmed16990140 Pubmed17478680 Pubmed8825650 Pubmed9701566 Reactome Database ID Release 43210500 Reactome, http://www.reactome.org ReactomeREACT_12591 Reviewed: Kavalali, E, 2008-04-24 16:31:34 PathwayStep3249 PathwayStep3255 PathwayStep3254 PathwayStep3253 PathwayStep3252 PathwayStep3251 PathwayStep3250 glutamine + H2O => glutamate + NH4+ [GLS] release of L-Glutamate at the synapse L-Glutamate uptake by neurons L-Glutamate loading of synaptic vesicle Glutamate synaptic vesicle docking and priming Transport of L-Glutamine (cytosol) to mitochondrial matrix Tranport of L-Glutamate (mitochondrial matrix) to cytosol L-Glutamine transport into neurons