Glutamate

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Glutamate is an amino acid that is the main excitatory transmitter in the brain and spinal cord, and it has been calculated that it is the transmitter responsible for 75% of the excitatory transmission in the brain.

Glutamate is formed by reductive amination of the Krebs cycle intermediate α-ketoglutarate in the cytoplasm.

Contents

Receptors

Metabotropic receptors

The metabotropic receptors are serpentine G protein-coupled receptors that increase intracellular IP3 and DAG levels or decrease intracellular cAMP levels. Eleven subtypes identified; all decrease cAMP or increase IP3 and DAG, except one, which increases cAMP.

Ionotropic receptors

The ionotropic receptors are ligand-gated ion channels that resemble the nicotinic cholinergic receptors and the GABA and glycine receptors. The receptors were thought to be pentamers. There are three general types:

  1. Kainate receptors
  2. AMPA receptors
  3. NMDA receptors

Kainate receptors

Simple ion channels that, when open, permit Na+ influx and K+ efflux.

AMPA receptors

Ions channels that mediate fast synaptic transmission in the CNS. The allow the movement of Na+ and K+ but are impermeable to Ca2+.

NMDA receptors

Also a cation channel, but it permits passage of relatively large amounts of Ca2+, and has several important features:

  • Glycine facilitates its function by binding to it.
  • When glutamate binds to it, it opens, but its channel is blocked by an Mg2+ ion. This block is removed only when the neuron containing the receptor is partially depolarized .
  • Phencyclidine and ketamine bind to another site inside the channel.

NMDA receptors are prevalent in the hippocampus, where the blockade of these channels prevents long term potentiation leading to the theory that these channels are involved in learning and memory.

Glutamate Excitotoxicity

High concentrations of glutamate produce neuronal cell death. The mechanisms are still being investigated. It is thought that in influx of Ca2+ triggered cell death, and maybe responsible for the damage seen after ischemia or hypoglycemia in which massive amounts of glutamate are released with impaired reuptake.

More recently, it has been proposed that local depletion of Na+ and K+, as well as small but significant elevations of extracellular Zn2+ may also be factors that can activate both necrotic and pro-apoptotic cascades. (Frandsen & Schousboe, 2002)

References

  1. Frandsen A, Schousboe A. AMPA receptor-mediated neurotoxicity: role of Ca2+ and desensitization. Neurochem Res 2003;28(10):1495-9.
  2. Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL. Goodman & Gilman's the pharmacological basis of therapeutics. 11th / ed. New York: McGraw-Hill; 2006.
  3. Katzung BG. Basic & clinical pharmacology. 10th ed. New York: McGraw-Hill Medical; 2007.
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