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Glutamate Neurotransmitter Release Cycle

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-210500

PubChem

R-HSA-210500

Description

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.

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 16 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O00341	Excitatory amino acid transporter 5	EAAT5 SLC1A7	view
O14795	Protein unc-13 homolog B	UNC13 UNC13B	view
O75145	Liprin-alpha-3	KIAA0654 PPFIA3	view
O75334	Liprin-alpha-2	PPFIA2	view
O75335	Liprin-alpha-4	KIAA0897 PPFIA4	view
O94925	Glutaminase kidney isoform, mitochondrial	GLS GLS1 KIAA0838	view
P21579	Synaptotagmin-1	SVP65 SYT SYT1	view
P43003	Excitatory amino acid transporter 1	EAAT1 GLAST GLAST1 SLC1A3	view
P43004	Excitatory amino acid transporter 2	EAAT2 GLT1 SLC1A2	view
P43005	Excitatory amino acid transporter 3	EAAC1 EAAT3 HEAAC1 SLC1A1	view

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