Glutamate Management
Lindsey Aune and Jim Hutchins
The Importance of Glutamate Management
Glutamate is the most widely distributed neurotransmitter in the human brain. About 40% of presynaptic terminals release glutamate, and about 90% of postsynaptic contacts in the brain have glutamate receptors.
Glutamate plays many important roles in our brain. However, in large amounts glutamate can also kills neurons. If a blood vessel gets occluded, there is a loss of blood supply (ischemia) in the brain. The neurons and glial cells that are killed in the immediate area are called the ischemic core. Surrounding the core, there will be a spreading wave of damage this is called the ischemic penumbra. Because (in general) glutamate is an excitatory neurotransmitter, this phenomenon is known as excitotoxicity. As neurons die in the ischemic core, they spill glutamate into the extracellular space. This glutamate diffuses away from the site of damage and activates glutamate receptors nearby. This glutamate can cause the death of these nearby neurons, repeating the process over and over again as the area of damage spreads widely from a relatively small initial area.
Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris luctus tortor metus, nec porttitor augue posuere eget. Ut sed orci id velit mollis pellentesque. Donec posuere ullamcorper ultrices. Vivamus dictum elit ut nisi porta, eget egestas tortor pretium. Donec tellus dolor, efficitur eget sapien vitae, posuere placerat leo. Mauris laoreet magna et tortor ornare, et sollicitudin enim hendrerit. Nunc sit amet turpis purus. Fusce pharetra lorem nec venenatis rutrum. Proin hendrerit neque non rutrum fermentum. Maecenas ac consequat elit. Ut consequat vel tortor ac maximus. Quisque vitae pretium eros.
Ut quis mauris quis mi varius elementum sit amet non enim. Quisque elementum, tellus ac imperdiet auctor, urna massa tristique lorem, vitae tristique justo enim in justo. Nullam ante nisl, molestie sed lacus ultricies, convallis auctor diam. Mauris viverra nulla faucibus imperdiet ultrices. Ut facilisis rutrum sapien, eu tincidunt orci semper id. Curabitur nisi est, volutpat ut tincidunt ut, vehicula eu erat. Integer rhoncus luctus odio vitae venenatis. Nulla viverra risus a dui accumsan, nec aliquam arcu egestas. Proin eu odio in nunc aliquam viverra vitae non enim. Aliquam id turpis id lectus finibus imperdiet. Cras id felis augue. Vestibulum vitae lorem non turpis scelerisque tempus sed varius sem. Sed mollis scelerisque eros.
Duis iaculis tortor orci, in blandit ipsum porttitor eu. Sed sit amet augue vel eros semper dictum ac vel elit. Donec vitae finibus erat. Mauris in velit vitae quam finibus ultricies non nec nulla. Sed enim est, venenatis vitae luctus ut, convallis quis ligula. Morbi egestas ac lacus vitae iaculis. Praesent eu erat risus. Suspendisse hendrerit, leo vel faucibus consectetur, justo dui lobortis elit, a luctus mi ex sit amet odio. Aenean porta, risus eget volutpat finibus, mauris elit ultrices sem, at pellentesque augue turpis in enim.
The Glutamatergic Synapse
Now we’re ready to consider the entire cycle of glutamate and glutamine at the glutamatergic synapse. Glutamate released from the presynaptic neuron can activate both AMPA and NMDA receptors (AMPAR, blue; NMDAR, silver) on the postsynaptic neuron in a controlled fashion. Because excess glutamate in the synapse can become toxic for neurons, excess glutamate is taken up by the astrocyte (cell shaded brown) using the excitatory amino acid transporter 1 (EAAT1) or 2 (EAAT2).
Once safely inside the astrocyte, glutamate’s hydroxyl group is removed and replaced with an amino group to form glutamine. Because glutamine has an amino group instead of a hydroxyl group the glutamine can no longer dock at NMDA receptors (where the glutamate would previously dock)- making it non toxic to the neuron. The enzyme that accomplishes this change is glutamine synthase (also called glutamine synthetase).
Then, a transporter called the sodium neutral amino acid transporter 3 (SNAT3) carries glutamine into the extracellular space between the astrocyte and neuron. The export of glutamine is coupled to the export of Na+ which places this protein carrier in the co-transport or symport category.
Now glutamine, unable to bind to the NMDA receptor making it non toxic to the post-synaptic neuron, can be transported into the pre-synaptic neuron by a “brother” of SNAT3 known as SNAT1, also known as SLC38A1. SNAT1 is also a co-transporter carrier protein and operates in a similar fashion, bringing in glutamine and using Na+ to drive the process. (Note that in this case, Na+ is being brought into the neuron and must later be removed by the ATP-requiring sodium/potassium pump.) The mitochondrial enzyme glutaminase replaces the amino group on glutamine with a hydroxyl group, reforming glutamate once it’s safely inside the neuron.
The glutamate thus formed can be packaged into vesicles by another transporter. In this case, the vesicular glutamate transporter (VGLUT) carries in a glutamate and exchanges it for a hydrogen ion (H+). That places the VGLUT into the category of exchangers or antiport transporters. Vesicles are made acidic by a separate ATP-requiring hydrogen ion (proton, H+) pump, not shown here; in this way, H+ runs down its concentration gradient and this energy is used to bring glutamate from where it is at low concentration to where it is at high concentration inside the vesicle. This process requires energy, because it reduces entropy, and that energy is supplied by the H+ gradient (originally established by the proton pump).
Then, as explained elsewhere, glutamate can be released from vesicles at the synapse and the cycle begins again.