Glutamate, also known as glutamic acid, is one of the principal excitatory neurotransmitters in the human central nervous system (CNS). It is the most abundant neurotransmitter in vertebrates and is involved in every major excitatory function, accounting in total for well over 90% of the synaptic connections in the human brain.
Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory.
The receptors for glutamate can be divided into metabotropic and ionotropic glutamate receptors. Ionotopic glutamate receptors fall into three major classes, known as AMPA receptors (GluA1-GluA4), NMDA receptors (GluN1-GluN3), and kainate receptors (GluK1-GluK5).
Glutamate is a major constituent of a wide variety of proteins which makes it one of the most abundant amino acids in the human body. It also serves as a metabolic precursor for the neurotransmitter GABA, the main inhibitory neurotransmitter.
Glutamate generally exists as a negatively-charged carboxylate at pH values above 4.
There are two categories of glutamate receptors, named for the mechanism that gives rise to the postsynaptic current; ionotropic and metabotropic. Ionotropic receptors work via the movement of ions in and out on ligand-gated ion channels. Metabotropic receptors work via their activation of secondary messenger chemicals. These chemicals eventually induce the postsynaptic current, either through their own action or by activating the ligand-gated ion channels.
Drugs targeting the glutamate system
A glutamate agonist is a chemical that binds to and activates a glutamate receptor and triggers a response, displaying full efficacy at that receptor. An example of this is theanine, a weak agonist of the NMDA receptor.
- Positive Allosteric Modulators
A positive allosteric modulator is a substance which indirectly influences the effects of an agonist at a receptor, by binding to a site distinct from that of the agonist binding site. They usually induce a structural change in the receptor structure. Many nootropics and ampakine (a class of compounds known to enhance attention span and alertness) drugs are positive modulators of the AMPA glutamate receptor. These include piracetam, aniracetam and unifiram.
A glutamate receptor antagonist is a type of receptor drug that inhibits action at glutamate receptors. Ethanol acts as an antagonist of the NMDA, AMPA and kainate glutamate receptors, along with several antiepileptic drugs. The nootropic compound theanine is an antagonist of the AMPA and kainate receptors. Many dissociative drugs are antagonists of the NMDA glutamate receptor, including ketamine, MXE, PCP and DXM. Tramadol and ibogaine are dual antagonists of the NMDA glutamate receptor and opioid receptors.
- Negative Allosteric Modulators
A negative allosteric modulator is a substance which indirectly influences the effects of an inverse agonist at a receptor, by binding to a site distinct from that of the inverse agonist binding site. Usually they induce a structural change in the receptor structure. Antiepileptic drugs are also found in this class.
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