Pathway: Glutamate Neurotransmitter Release Cycle
Reactions in pathway: Glutamate Neurotransmitter Release Cycle :
Glutamate Neurotransmitter Release Cycle
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.
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.
Chemical synapses are specialized junctions that are used for communication between neurons, neurons and muscle or gland cells. The synapse involves a presynaptic neuron and a postsynaptic neuron, muscle cell or glad cell. The pre and the postsynaptic cell are separated by a gap (space) of 20 to 40 nm called the synaptic cleft. The signals pass in a single direction from the presynaptic to postsynaptic neuron (cell). The presynaptic neuron communicates via the release of neurotransmitter which bind the receptors on the postsynaptic cell. The process is initiated when an action potential invades the terminal membrane of the presynaptic neuron.
Action potentials occur in electrically excitable cells such as neurons and muscles and endocrine cells. They are initiated by the transient opening of voltage dependent sodium channels, causing a rapid, large depolarization of membrane potentials that spread along the axon membrane.
When action potentials arrive at the synaptic terminals, depolarization in membrane potential leads to the opening of voltage gated calcium channels located on the presynaptic membrane. The external Ca2+ concentration is approximately 10-3 M while the internal Ca2+ concentration is approximately 10-7 M. Opening of calcium channels causes a rapid influx of Ca2+ into the presynaptic terminal. The elevated presynaptic Ca2+ concentration allows synaptic vesicles to fuse with the plasma membrane of the presynaptic neuron and release their contents, neurotransmitters, into the synaptic cleft. These diffuse across the synaptic cleft and bind to specific receptors on the membrane of the postsynaptic cells. Activation of postsynaptic receptors upon neurotransmitter binding can lead to a multitude of effects in the postsynaptic cell, such as changing the membrane potential and excitability, and triggering intracellular signaling cascades.
Action potentials occur in electrically excitable cells such as neurons and muscles and endocrine cells. They are initiated by the transient opening of voltage dependent sodium channels, causing a rapid, large depolarization of membrane potentials that spread along the axon membrane.
When action potentials arrive at the synaptic terminals, depolarization in membrane potential leads to the opening of voltage gated calcium channels located on the presynaptic membrane. The external Ca2+ concentration is approximately 10-3 M while the internal Ca2+ concentration is approximately 10-7 M. Opening of calcium channels causes a rapid influx of Ca2+ into the presynaptic terminal. The elevated presynaptic Ca2+ concentration allows synaptic vesicles to fuse with the plasma membrane of the presynaptic neuron and release their contents, neurotransmitters, into the synaptic cleft. These diffuse across the synaptic cleft and bind to specific receptors on the membrane of the postsynaptic cells. Activation of postsynaptic receptors upon neurotransmitter binding can lead to a multitude of effects in the postsynaptic cell, such as changing the membrane potential and excitability, and triggering intracellular signaling cascades.
The human brain contains at least 100 billion neurons, each with the ability to influence many other cells. Clearly, highly sophisticated and efficient mechanisms are needed to enable communication among this astronomical number of elements. This communication occurs across synapses, the functional connection between neurons. Synapses can be divided into two general classes: electrical synapses and chemical synapses. Electrical synapses permit direct, passive flow of electrical current from one neuron to another. The current flows through gap junctions, specialized membrane channels that connect the two cells. Chemical synapses enable cell-to-cell communication using neurotransmitter release. Neurotransmitters are chemical agents released by presynaptic neurons that trigger a secondary current flow in postsynaptic neurons by activating specific receptor molecules. Neurotransmitter secretion is triggered by the influx of Ca2+ through voltage-gated channels, which gives rise to a transient increase in Ca2+ concentration within the presynaptic terminal. The rise in Ca2+ concentration causes synaptic vesicles (the presynaptic organelles that store neurotransmitters) to fuse with the presynaptic plasma membrane and release their contents into the space between the pre- and postsynaptic cells.