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Glutamate (neurotransmitter): definition and functions

Glutamate (neurotransmitter): definition and functions

October 21, 2020

The glutamate mediates most excitatory synapses of the Central Nervous System (CNS). It is the main mediator of sensory, motor, cognitive, emotional information and intervenes in the formation of memories and in their recovery, being present in 80-90% of the brain's synapses.

In case it is little merit all this, also intervenes in neuroplasticity, learning processes and is the precursor of GABA - the main inhibitory neurotransmitter of the CNS-. What else can a molecule be asked for?

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 powerful pharmacological target in various diseases.


It should also be mentioned that given the complexity of its receptors, this is one of the most complicated neurotransmitters to study.

The synthesis process

The synthesis process of glutamate has its beginning in the Krebs cycle, or cycle of tricarboxylic acids. The Krebs cycle is a metabolic path or, for us to understand, 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 clock, in which each gear fulfills a function and the simple failure of a piece can cause the clock to spoil or not mark the time well. The cycles in biochemistry are the same. A molecule, by means of continuous enzymatic reactions - clock gears -, changes its form and composition with the aim of giving 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.


It is also worth mentioning another quite significant precursor: glutamine. When the cell releases glutamate into the extracellular space, the astrocytes - a type of glial cell - recover this glutamate, which, through an enzyme called glutamine synthetase, will become glutamine. Then, the astrocytes release glutamine, which is recovered again by the neurons to be transformed back into glutamate . And possibly more than one will ask the following: And if they have to return glutamine back to glutamate in the neuron, why does the astrocyte turn glutamine into poor glutamate? Well, I do not know either. Perhaps it is that astrocytes and neurons do not agree or maybe Neuroscience is that complicated. In any of the cases, I wanted to review the astrocytes because their collaboration represents 40% of the turnover of glutamate, which means that most of the glutamate is recovered by these glial cells .


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

The glutamate receptors

As we are often taught, each neurotransmitter has its receptors in the postsynaptic cell . The 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 it is located in the receptor. In neurons we usually place the receptors in the postsynaptic cells, although it does not have to be that way in reality.

We are also taught in the first race that there are two types of main receptors: ionotropic and metabotropic. Ionotropics are those in which when their ligand is bound-the "key" of the receptor-they open channels that allow the passage of ions into the cell. Metabotropics, on the other hand, when the ligand is bound, cause changes in the cell by means of second messengers. In this review I will talk about the main types of ionotropic receptors of Glutamate, although I recommend the study of the bibliography for the knowledge of metabotropic receptors. Here I quote the main ionotropic receptors:

  • NMDA receiver.
  • AMPA receiver.
  • Kainado receiver.

The NMDA and AMPA receptors and their close relationship

It is believed that both types of receptors are macromolecules formed by four transmembrane domains -that is, they are formed by four subunits that traverse the lipid bilayer of the cell membrane- and both are glutamate receptors that will open up positively charged cation channels. 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; while NMDA receptors can not be activated until the neuron has a membrane potential of about -50mV - a neuron when inactivated is usually around -70mV. Second, the step cations will be different in each case. AMPA receptors achieve much higher membrane potentials than NMDA receptors, which coalesce much more modestly. In return, NMDA receivers will achieve much more sustained activations in time than those of AMPA. So, those of AMPA are activated quickly and produce stronger excitatory potentials, but they are deactivated quickly . And those of NMDA are slow to activate, but they manage to keep the excitatory potentials they generate much longer.

To understand it better, let's imagine that we are soldiers and that our weapons represent the different receivers. Imagine that the extracellular space is a trench. We have two types of weapons: revolver and grenades. The grenades are simple and quick to use: you remove the ring, the strips and wait for it to explode. They have a lot of destructive potential, but once we've thrown them all away, it's over. The revolver is a weapon that takes its time to load because you have to remove the drum and put the bullets 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 the NMDA receivers and our grenades are the AMPA ones.

The excesses of glutamate and its dangers

They say that in excess nothing is good and in the case of glutamate is fulfilled. Then we will mention some pathologies and neurological problems in which an excess of glutamate is related .

1. Glutamate analogs can cause exotoxicity

Glutamate-like drugs - that is, they have the same function as glutamate - like NMDA - to which the NMDA receptor owe its name - can cause high doses neurodegenerative effects in the most vulnerable brain regions 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 of some animals and plants exert their effects through the nerve pathways of glutamate. An example is the poison of the seeds of Cycas Circinalis, a poisonous plant that we can find on the Pacific island of Guam. This poison caused a great prevalence of Amyotrophic Lateral Sclerosis in this island in which 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 heart attack , cardiac arrest, pre / perinatal hypoxia. In these events in which there is a lack of oxygen in the brain tissue, the neurons remain in a state of permanent depolarization; because of different biochemical processes. This leads to the permanent release of glutamate from the cells, with the subsequent sustained activation of the glutamate receptors. The NMDA receptor is especially permeable to calcium compared to other ionotropic receptors, and excess calcium leads to neuronal death. Therefore, the hyperactivity of glutamatergic receptors leads to neuronal death due to the increase of intraneuronal calcium.

4. Epilepsy

The relationship between glutamate and epilepsy is well documented. It is considered that epileptic activity is especially related to AMPA receptors, although as epilepsy progresses, NMDA receptors become important.

Is glutamate good? Is glutamate bad?

Usually, when one reads this type of text, it ends up humanizing the molecules by labeling them "good" or "bad" - that has a name and is called anthropomorphism, very fashionable back in medieval times. Reality is far from these simplistic judgments.

In a society in which we have generated a concept of "health" it is easy for some of the mechanisms of nature to make us uncomfortable. The problem is that nature does not understand "health". We have created that through medicine, pharmaceutical industries and psychology. It is a social concept, and like any social concept is subject to the progress of societies, be it human or scientific. The advances show that glutamate is related to a good number of pathologies like Alzheimer's or Schizophrenia.This is not an evil eye of evolution to the human being, rather it is a biochemical mismatch of a concept that nature still does not understand: human society in the 21st century.

And as always, why study this? In this case I think the answer is very clear. Due to the role of glutamate in various neurodegenerative pathologies, it results in 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 you could write an entry exclusively on this, are Alzheimer's disease and schizophrenia. Subjectively, I find the search for new drugs for schizophrenia especially interesting for basically two reasons: the prevalence of this disease and the health cost involved; and the adverse effects of current antipsychotics that in many cases hinder therapeutic adherence.

Text edited and edited by Frederic Muniente Peix

Bibliographic 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. //dx.doi.org/10.1038/sj.npp.1301559
  • Hardingham, G. & Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signaling: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11 (10), 682-696. //dx.doi.org/10.1038/nrn2911
  • Hardingham, G. & Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signaling: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11 (10), 682-696. //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. //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. //dx.doi.org/10.1098/rstb.2013.0601

2-Minute Neuroscience: Glutamate (October 2020).


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