Neurotransmitters: Glutamate

Glutamate Production and Packaging

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Postsynaptic Glutamate Receptors

Ionotropic glutamate receptors include:

• α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
• N-methyl-D-aspartate (NMDA) receptors
• kainic acid receptors

Metabotropic glutamate receptors include eight different types (and many different subtypes). The main types are abbreviated mGluR1 through mGluR8.

The AMPA Glutamate Receptor

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The NMDA Glutamate Receptor

As explained earlier, NMDA glutamate receptors are coincidence detectors that play a key role in the processes of learning and memory.

Glutamate released from the presynaptic terminal diffuses across the synaptic cleft and binds to the AMPA receptor, opening a ligand-gated sodium ion (Na⁺) channel. This slightly depolarizes the postsynaptic neuron.

The NMDA receptor has a more complex mechanism. The neuron holds a voltage across the cell membrane, even when it’s not active. This is called the resting membrane potential. When the voltage rises from the normal, negative value, the NMDA receptor can allow calcium ions (Ca²⁺) to flow into the neuron.

A small amount of Ca²⁺ entry results in the activation of key intracellular signaling pathways such as those needed for the strengthening of synapses in learning and memory processes. But when nearby neurons die, the uncontrolled flood of glutamate and the larger amount of Ca²⁺ entry through the NMDA receptor which results kills neurons. Thus, a small amount of glutamate is essential; a slightly larger amount is deadly. It’s clear the neuron and astrocyte need to work together to limit the amount of glutamate that is available within the synaptic cleft.

How Does Glutamate Bind to the NMDA Receptor?

The mechanism of glutamate binding to the NMDA receptor is a good example of how neurotransmitter receptors work. The NMDA receptor is a protein which is, like all proteins, formed from a string of amino acids joined by strong bonds called peptide bonds. Each amino acid can be indicated by a single letter code. Then, a number following the letter indicates its position in the amino acid chain. These numbers are assigned sequentially, in the order that amino acids are added by tRNA at the ribosome. When a protein becomes folded, the folding process does not necessarily respect this sequential order.

In this example, serine-486 (S486), threonine-488 (T488), arginine-493 (R493), serine-664 (S664), threonine-655 (T655), and aspartate-706 (D706) all come together to form a pocket which can bind glutamate and no other substance.

This pocket is lined with hydrophilic amino acid residues. These residues are hydrophilic because they are able to form hydrogen bonds with water and other hydrophilic compounds, like glutamate.

Hydrogen bonds are shown as dotted lines in the illustrations, indicating their transient and half-hearted nature.

Within the lining of the pocket, the pattern of hydrogen bonding in the amino acid residues exactly matches the hydrogen bonding properties of the glutamate molecule. For example, wherever the glutamate molecule has a negatively-charged, hydrogen-donating carboxylic acid (—COOH) group, the receptor protein provides one or more positively-charged, hydrogen-accepting amino (—NH₂) groups. When the carboxylic acid group donates its hydrogen, or partially donates it, it becomes —COO^–. When the amino group accepts a hydrogen, or partially accepts it, it becomes —NH₃⁺. The partial, or transient, attraction between these partial, or transient, opposite charges is the essence of hydrogen bonding. In this way, glutamate is held in the NMDA receptor pocket and the NMDA receptor changes shape to allow the passage of Na⁺ or Na⁺ and Ca²⁺ ions.

Why Doesn’t Glutamine Bind to the NMDA Receptor?

By simpling removing a hydroxyl (—OH) group, and replacing it with an amino (—NH₂) group, glutamate becomes glutamine and completely changes its hydrogen bonding properties.

Now it no longer fits within the NMDA receptor pocket (red Xs). Since it cannot bind to the receptor, it cannot trigger toxic levels of Ca²⁺ entry and can be passed harmlessly through the extracellular space.

Metabotropic Glutamate Receptors

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Glutamate Removal and Recycling

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