Glutamate (neurotransmitter): definition and functions

What is the function of glutamate in our Central Nervous System?

The glutamate mediates most of the excitatory synapses of the Central Nervous System (CNS). It is the main mediator of sensory, motor, cognitive and emotional information and is involved in memory formation and retrieval, being present in 80-90% of brain synapses.

As if all this were not enough, it is also involved in neuroplasticity, learning processes and is the precursor of GABA -the main inhibitory neurotransmitter of the CNS-. What more can you ask of a molecule?

What is glutamate?

Possibly has been one of the most extensively studied neurotransmitters in the nervous system.. In recent years its study has been increasing due to its relationship with various neurodegenerative pathologies (such as Alzheimer's disease), which has made it a potent pharmacological target in various diseases.

It is also worth mentioning that given the complexity of its receptors, this is one of the most complicated neurotransmitters to study.

The synthesis process

The process of glutamate synthesis begins in the Krebs cycle, or tricarboxylic acid cycle. The Krebs cycle is a metabolic pathway, or, to put it another way, a succession of chemical reactions with the same chemical structure as the Krebs cycle, a succession of chemical reactions in order to produce cellular respiration in the mitochondria.. A metabolic cycle can be understood as the mechanism of a watch, in which each gear fulfills a function and the simple failure of a part can cause the watch to break down or not to keep time. The cycles in biochemistry are the same. A molecule, by means of continuous enzymatic reactions - the gears of the clock - changes its shape and composition in order to give rise to a cellular function. The main precursor of glutamate will be alpha-ketoglutarate, which will receive an amino group by transamination to become glutamate.

Another significant precursor is also worth mentioning: glutamine. When the cell releases glutamate into the extracellular space, the astrocytes - a type of glial cell - recover this glutamate which, by means of an enzyme called glutamine synthetase, will be converted into glutamine. Then, the astrocytes release the glutamine, which is retrieved again by the neurons to be transformed back into glutamate.. And possibly more than one will ask the following question: And if glutamine is to be converted back into glutamate in the neuron, why does the astrocyte convert the poor glutamate back into glutamine? Well, I don't know either. Maybe it is that astrocytes and neurons do not agree or maybe it is that Neuroscience is so complicated. In either case, I wanted to review the astrocytes because their collaboration accounts for 40% of the turnover of glutamate turnover, which means that most of the glutamate most of the glutamate is recovered by these glial cells..

There are other precursors and other pathways by which glutamate is recovered and released into the extracellular space. For example, there are neurons that contain a specific glutamate transporter -EAAT1/2- that directly retrieve glutamate to the neuron and allow termination of the excitatory signal. For further study of glutamate synthesis and metabolism I recommend reading the literature.

Glutamate receptors

As we are usually taught each neurotransmitter has its receptors in the postsynaptic cell.. Receptors, located in the cell membrane, are proteins to which a neurotransmitter, hormone, neuropeptide, etc., binds to give rise to a series of changes in the cellular metabolism of the cell in which the receptor is located. In neurons, we generally locate receptors in postsynaptic cells, although this does not have to be the case in reality.

We are also taught in the first year of our studies that there are two main types of receptors: ionotropic and metabotropic. Ionotropic receptors are those in which, when their ligand - the "key" of the receptor - binds, they open channels that allow the passage of ions into the cell. Metabotropics, on the other hand, when the ligand binds, cause changes in the cell by means of second messengers. In this review I will discuss the main types of Glutamate ionotropic receptors, although I recommend the study of the literature for the knowledge of metabotropic receptors. The following are the main ionotropic receptors:

• NMDA receptor.
• AMPA receptor.
• Kainate receptor.

The NMDA and AMPA receptors and their close relationship

Both types of receptors are believed to be macromolecules consisting of four transmembrane domains - that is, they are made up of four subunits that cross the lipid bilayer of the cell membrane - and both are glutamate receptors that will open cation channels - positively charged ions. But, even so, they are significantly different.

One of their differences is the threshold at which they are activated. First, AMPA receptors are much faster to activate; whereas NMDA receptors cannot be activated until the neuron has a membrane potential of about -50mV - a neuron when inactivated is usually at about -70mV. Secondly, the cation step will be different in each case. AMPA receptors will achieve much higher membrane potentials than NMDA receptors, which will cooperate much more modestly. In return, NMDA receptors will achieve much more sustained activations over time than AMPA receptors. Therefore, AMPA receptors activate rapidly and produce stronger excitatory potentials, but deactivate rapidly.. And the NMDA ones take longer to activate, but manage to sustain much longer the excitatory potentials they generate.

To understand it better, let's imagine that we are soldiers and that our weapons represent the different receptors. Let's imagine that the extracellular space is a trench. We have two types of weapons: revolver and grenades. Grenades are simple and quick to use: you remove the pin, throw it and wait for it to explode. They have a lot of destructive potential, but once we've thrown them all, it's over. The revolver is a weapon that takes a long time to load because you have to remove the drum and put the bullets in one by one. But once we have loaded it we have six shots with which we can survive for a while, although with much less potential than a grenade. Our brain revolvers are NMDA receptors and our grenades are AMPA receptors.

Excess glutamate and its dangers

They say that nothing is good in excess, and in the case of glutamate this is true. In the case of glutamate, this is true. Here are some pathologies and neurological problems in which an excess of glutamate is involved.

1. Glutamate analogues can cause exotoxicity.

Drugs analogous to glutamate - that is, performing the same function as glutamate - such as NMDA - to which the NMDA receptor owes its name - can cause neurodegenerative effects in the most vulnerable brain regions at high doses. at high doses can cause neurodegenerative effects in the most vulnerable brain regions, such as the arcuate nucleus of the hypothalamus and the such as the arcuate nucleus of the hypothalamus. The mechanisms involved in this neurodegeneration are diverse and involve different types of glutamate receptors.

2. Some neurotoxins that we can ingest in our diet exert neuronal death through excess glutamate.

Different poisons from some animals and plants exert their effects through glutamate nerve pathways. An example is the poison from the seeds of Cycas circinalis, a poisonous plant found on the Pacific island of Guam. This poison caused a high prevalence of Amyotrophic Lateral Sclerosis in this island where its inhabitants ingested it daily believing it to be benign.

3. Glutamate contributes to neuronal death by ischemia

Glutamate is the main neurotransmitter in acute brain disorders such as myocardial infarction, cardiac arrest, pre/perinatal hypoxiacardiac arrest, cardiac arrest, pre/perinatal hypoxia. In these events in which there is a lack of oxygen in the brain tissue, neurons are kept in a state of permanent depolarization; due to different biochemical processes. This leads to the permanent release of glutamate from the cells, with subsequent sustained activation of glutamate receptors. The NMDA receptor is especially permeable to calcium compared to other ionotropic receptors, and excess calcium leads to neuronal death. Therefore, hyperactivity of glutamatergic receptors leads to neuronal death due to increased intraneuronal calcium.

4. Epilepsy

The relationship between glutamate and epilepsy is well documented. Epileptic activity is thought to be especially related to AMPA receptors, although as epilepsy progresses NMDA receptors become important.

Is glutamate good, and is glutamate bad?

Usually, when you read these kinds of texts you end up humanizing molecules by labeling them as "good" or "bad" -that has a name and it's called anthropomorphismwhich was very fashionable in medieval times. Reality is far from such simplistic judgments.

In a society in which we have generated a concept of "health", it is easy for some of nature's mechanisms to make us uncomfortable. The problem is that nature does not understand "health". We have created it ourselves through medicine, pharmaceutical industries and psychology. It is a social concept, and like all social concepts, it is subject to the progress of society, whether human or scientific. Advances show that glutamate is related to a number of pathologies such as Alzheimer's or schizophrenia. such as Alzheimer's disease or schizophrenia. This is not an evil eye of evolution to the human being, rather it is a biochemical maladaptation of a concept that nature still does not understand: human society in the XXI century.

And as always, why study this? In this case I think the answer is very clear. Because of the role of glutamate in several neurodegenerative pathologies, it is an important -although also complex- pharmacological target.. Some examples of these diseases, although we have not talked about them in this review because I think that an entry could be written exclusively about this, are Alzheimer's disease and Schizophrenia. Subjectively, I find the search for new drugs for schizophrenia particularly interesting for two basic reasons: the prevalence of this disease and the health care costs involved; and the adverse effects of current antipsychotics, which in many cases hinder therapeutic adherence.

Text corrected and edited by Frederic Muniente Peix.

Bibliographical references:

Books:

• Siegel, G. (2006). Basic neurochemistry. Amsterdam: Elsevier.

Articles:

• Citri, A. & Malenka, R. (2007). Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms.Neuropsychopharmacology, 33(1), 18-41. http://dx.doi.org/10.1038/sj.npp.1301559
• Hardingham, G. & Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11(10), 682-696. http://dx.doi.org/10.1038/nrn2911
• Hardingham, G. & Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11(10), 682-696. http://dx.doi.org/10.1038/nrn2911
• Kerchner, G. & Nicoll, R. (2008). Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nature Reviews Neuroscience, 9(11), 813-825. http://dx.doi.org/10.1038/nrn2501
• Papouin, T. & Oliet, S. (2014). Organization, control and function of extrasynaptic NMDA receptors.Philosophical Transactions Of The Royal Society B: Biological Sciences, 369(1654), 20130601-20130601. http://dx.doi.org/10.1098/rstb.2013.0601