Introduction Glutamate is an amino acid that functions as a neurotransmitter in the central nervous system, and is the chief excitatory neurotransmitter there, present in nearly more than half of all neurons. It is also a precursor of GABA (Gama-Aminobutyric Acid) which has the exact opposite effect, as it is the major inhibitory neurotransmitter in the central nervous system. Glutamate was first discovered as a food component -Monosodium Glutamate- that played a role in flavor; which implies that glutamate is present in our dietary intake.
However, its discovery as a neurotransmitter took place in 1952 by T. Hayoshi who was intrigued by experiments of Glutamate injections effect on dogs. Glutamate can have different effects on post-synaptic neurons depending on the receptor type, and it plays a role in learning and memory as well. In order for Glutamate to affect cells, it needs to bind to the receptors present on the surface of cells because it does not activate receptors when it is inside the cell.
In addition to being a neurotransmitter, Glutamate, like any other amino acid, functions in the synthesis of proteins, detoxification of ammonia and many metabolic pathways for energy production. Synthesis, Transportation, Uptake and ReproductionGlutamate is one of the nonessential amino acids that can be synthesized in the body. Although Glutamate, as mentioned earlier, can be consumed in our diet, it cannot go across the blood brain barrier so it needs to be synthesized in neurons.
Glutamate synthesis happens in a cycle called the Glutamate-Glutamine cycle. Termination of Glutamates effect occurs by its uptake from the synaptic cleft by special transporter proteins called Excitatory Amino Acid Transporters (EAATs), that are present on presynaptic nerve terminals and glial cells, like astrocytes. Glutamate, after its uptake into Glial cells, is converted to Glutamine by glutamine synthetase using ATP as a source of energy. It is important to convert it to Glutamine because Glutamine cannot attach to Glutamate’s receptors and its presence in the extracellular fluid is not as harmful. Glutamine is then transported from glial cells into presynaptic terminals and is there converted to Glutamate and Ammonia by the help of the mitochondrial enzyme glutaminase that uses ATP as energy to catalyze this reaction.
Glutamate is then stored into vesicles in nerve terminals by the aid of Vesicular Glutamate Transporters (VGLUTs). It is then released from the terminal by exocytosis. Once released, it attaches to its post-synaptic neuron receptors and then the cycle repeats as it is removed from there by EAATs once again. Glutamate can also be made from Alpha-Ketoglutarate, an intermediate in the Krebs cycle; which indicates that Glucose is indirectly used to synthesize Glutamate in neurons. Receptors Glutamate has two different types of receptors that are located on the surface of cells, ionotropic and metabotropic receptors. Each type is divided into groups.
Ionotropic receptors are ligand-gated ion channels that allow the passage of positively charged ions like sodium, potassium and calcium when Glutamate binds to them. Those receptors always cause excitatory post-synaptic potentials (EPSP) upon Glutamate binding, in other words, they always depolarize post synaptic membranes. These receptors were named after the materials that stimulate them, and they are: N-methyl-D-asparate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), Kainite, and Delta. AMPA and NMDA are present at the same synapse.
If a weak stimulus occurs, it activates only AMPA receptors that allow Sodium ions to enter, NMDA receptors are not activated because Magnesium ions prevent their opening during weak stimuli. If, on the other hand, a stronger stimulus takes places, it activates NMDA receptors and removes the Magnesium ion, allowing Sodium and Calcium ions to enter. Calcium ions, entering onky through NMDA receptors, act as second messengers that can cause an increase in the number of AMPA receptors. This increase in receptor number causes a stronger response to a specific stimulus on post synaptic neurons. Calcium also activates retrograde signals that cause the release of more neurotransmitters from presynaptic terminals causing a stronger stimulus. This is a mechanism that takes part in synaptic long term potentiation involved in memory.
The other three receptor groups are classified as metabotropic, G protein coupled Glutamate receptors (mGluR) which control the excitability of brain cells by regulating ion channels inside cells indirectly. These cause either excitatory (EPSP) or inhibitory post-synaptic potentials (IPSP) depending on their subtype. However, they produce a slower response in post synaptic neurons than ionotropic receptors.
After G proteins are activated by the metabotropic receptors, they communicate with ion channels or other effector proteins such as enzymes that cause ion channels to either open or close inside cells. These receptors were also found to play a role in controlling the excitability of neurons, transmission in synapses, synaptic plasticity that is involved in memory. Toxicity and disordersGlutamate is almost entirely present inside cells unless it is needed elsewhere, then it is released into the extracellular fluid to bind to its receptors. High concentrations of Glutamate in the extracellular fluid can have lethal effects due to its toxic nature.
Another factor that contributes to lethal effects is if the receptors for Glutamate are over sensitive and are activated by small quantities of it. One toxic effect is called excitotoxicity in which neurons are roused to death which is caused by over stimulation of the NMDA and AMPA receptors due to extreme release of Glutamate, which allows excessive entry of calcium ions into cells. High quantities of Glutamate can cause stroke, and contributes to a variety of neurodegenerative diseases like Alzheimer’s, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and epilepsy. It can also cause mental and psychological disorders like schizophrenia, autism, obsessive compulsive disorder (OCD) and depression.
Alzheimer’s is a neurodegenerative disease which is caused by over activation of NMDA receptors which causes increased inflow of Calcium ions into neurons which results in degradation of synapses and neurons and therefore loss of their job which is primarily involved in memory and learning. Other causes for Alzheimer’s disease are errors in the Glutamate-Glutamine cycle in which loss of the transporter protein that is used to transport Glutamate into vesicles (VGLUT) occurs. Another transporter protein that is damaged and contributes to Alzheimer’s disease is a the excitatory amino acid transporter 2 (EAAT), these are only some of the many other causes for Alzheimer’s disease.DrugsGlutamatergic drugs act by blocking different subtypes of Glutamate’s receptors or by regulating its transmission using various mechanisms.
For example, Riluzole enhances synaptic plasticity and is used to treat amyotrophic lateral sclerosis. Riluzole works by inhibiting voltage gated sodium channels, therefore, preventing the depolarization of the presynaptic membranes that release Glutamate. It also improves uptake of Glutamate by astrocytes, therefore it decreases the amount of Glutamate present in the extracellular fluid, eliminating its neurodegenerative effects.
Another drug that averts Glutamate’s release is Lamotrigine. It does so by blocking voltage gated Sodium, Potassium, and Calcium channels. Other drugs include Ketamine that doesn’t allow the entry of Sodium and Calcium ion through NMDA receptors, thus inhibiting their action. Memantine is another NMDA receptor antagonist drug used to treat Alzheimer’s symptoms.