Glutamate (neurotransmitter): definition and functions

the glutamate averages most central nervous system (CNS) excitatory synapses. It is the main mediator of sensory, motor, cognitive, emotional information and participates in the formation of memories and their recovery, being present in 80 to 90% of brain synapses.

As if all this had little merit, it is also involved in neuroplasticity, learning processes and is the precursor of GABA – the main inhibitory neurotransmitter of the CNS. What more could a molecule ask for?

What is glutamate?

perhaps has been one of the most studied neurotransmitters of the nervous system. In recent years, its study is 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 should also be mentioned that given the complexity of its receptors, it 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, so to speak, a succession of chemical reactions to produce cellular respiration in the mitochondria. A metabolic cycle can be understood as the mechanism of a clock, in which each gear performs a function and the simple failure of one part can cause the clock to break or not set the time correctly. The cycles of biochemistry are the same. A molecule, through continuous enzymatic reactions – the gears of the clock – changes shape and composition to give rise to cellular function. The main precursor of glutamate will be alpha-ketoglutarate, which will receive an amino group by transamination to become glutamate.

Another important precursor should also be mentioned: glutamine. When the cell releases glutamate into the extracellular space, astrocytes – a type of glial cell – collect this glutamate which, thanks to a glutamine synthetase, becomes glutamine. after, astrocytes release glutamine, which is taken up by neurons to be converted back into glutamate. And maybe more than one will ask the following: And if they have to return glutamine to glutamate to the neuron, why is the astrocyte giving it to convert poor glutamate to glutamine? Well, I don’t know either. Maybe it’s because astrocytes and neurons don’t agree, or maybe it’s because neuroscience is so complicated. In any case, I wanted to review the astrocytes because their collaboration represents 40% of the turnover of glutamate, which means that most of the glutamate is taken up by these glial cells.

There are other precursors and other pathways by which glutamate released into the extracellular space is recovered. For example, there are neurons that contain a specific glutamate transporter -EAAT1 / 2- which directly picks up glutamate from the neuron and allows the excitatory signal to terminate. For a more in-depth study of glutamate synthesis and metabolism, I recommend reading the literature.

Glutamate receptors

As they usually teach us, 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 usually locate receptors in postsynaptic cells, although this is not necessarily the case.

We are also often taught at the start of a degree that there are two main types of receptors: ionotropic and metabotropic. Ionotropes are those in which, when it binds to its ligand – the “key” to the receptor – open channels that allow ions to pass inside the cell. Metabotropes, on the other hand, when bound to the ligand, cause changes in the cell via second messengers. In this review, I will talk about the main types of ionotropic glutamate receptors, although I recommend studying the literature to find out about metabotropic receptors. Here are the main ionotropic receptors:

  • NMDA receiver.
  • AMPA receiver.
  • Cainado receiver.

NMDA and AMPA receptors and their close relationship

Both types of receptors are believed to be macromolecules made up 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 the cation channels – the ions. accused-. But still, they are very different.

One of their differences is the threshold at which they are activated. First, AMPA receptors are much faster to activate; while NMDA receptors will not be able to be activated until the neuron has a membrane potential of around -50mV – a neuron when inactivated is usually around -70mV. Second, the step cations will be different in each case. AMPA receptors would reach much higher membrane potentials than NMDA receptors, which will collaborate much more modestly. In return, the NMDA receptors will achieve much more sustained activations over time than the AMPA receptors. Therefore, those of AMPA activate quickly and produce stronger excitatory potentials, but they deactivate quickly. And those from NMDA take a long time to activate, but they manage to retain the excitatory potentials they generate much longer.

To better understand this, imagine that we are soldiers and that our weapons represent the different receptors. Imagine that the extracellular space is a trench. We have two types of weapons: the revolver and the grenades. Grenades are quick and easy to use: remove the ring, strip it, and wait for it to explode. They have a lot of destructive potential, but once we throw them all out it’s over. The revolver is a weapon that takes its time to load because you have to take out the drum and put the bullets one by one. But once we load it up we have six hits that we can survive with for a while, albeit with much less potential than a grenade. Our brain guns are NMDA receptors and our AMPA receptor grenades.

Excess glutamate and its dangers

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

1. Glutamate analogues may cause exotoxicity

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

2. Certain neurotoxins that we can ingest in our food cause neuronal death by excess glutamate

Different poisons of certain animals and plants exert their effects through the nerve pathways of glutamate. One 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 on this island where its inhabitants ingested it daily, judging it to be benign.

3. Glutamate contributes to neuronal death from ischemia

Glutamate is the main neurotransmitter in acute brain disorders such as heart attacks, Cardiac arrest, pre / perinatal hypoxia. In those events where there is a lack of oxygen in the brain tissue, the neurons remain in a state permanent depolarization; due to different biochemical processes. This leads to the permanent release of glutamate from the cells, with the subsequent sustained activation of glutamate receptors. The NMDA receptor is particularly permeable to calcium compared to other ionotropic receptors, and excess calcium leads to neuronal death. Therefore, overactivity of glutamatergic receptors leads to neuronal death due to increased intraneuronal calcium.

4. Epilepsy

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

Is glutamate good? Is Glutamate Bad?

Usually when you read this type of text you end up humanizing the molecules by labeling them “good” or “bad” – this has a name and is called anthropomorphism, very popular there in medieval times. . The reality is quite far from these simplistic judgments.

In a society where we have generated a concept of “health”, it is easy for certain mechanisms of nature to disturb us. The problem is, nature doesn’t understand “health”. We created it through medicine, the pharmaceutical industry and psychology. It is a social concept and, like any social concept, it is subject to the evolution of society, whether human or scientific. Progress shows that glutamate is associated with a number of pathologies like Alzheimer’s disease or schizophrenia. This is not an evil eye on evolution in humans, but rather a biochemical mismatch of a concept nature does not yet 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 that glutamate plays in various neurodegenerative pathologies, it results in an important pharmacological target – although it is also complex.. Alzheimer’s disease and schizophrenia are a few examples of these conditions, although we haven’t covered them in this review because I think an entry could be written exclusively on this topic. Subjectively, I find the search for new drugs against schizophrenia particularly interesting for two main reasons: the prevalence of this disease and the health cost it entails; and the adverse effects of current antipsychotics which in many cases hamper adherence.

Text edited and edited by Frederic Muniente Peix

Bibliographical references:


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


  • Citri, A. and Malenka, R. (2007). Synaptic plasticity: multiple forms, functions and mechanisms. Neuropsychopharmacology, 33 (1), 18-41.
  • Hardingham, G. and Bading, H. (2010). Synaptic signaling versus extrasinaptic NMDA receptors: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11 (10), 682-696.
  • Hardingham, G. and Bading, H. (2010). Synaptic signaling versus extrasinaptic NMDA receptors: implications for neurodegenerative disorders. Nature Reviews Neuroscience, 11 (10), 682-696.
  • Kerchner, G. and Nicoll, R. (2008). Silent synapses and emergence of a postsynaptic mechanism for LTP. Nature Reviews Neuroscience, 9 (11), 813-825.
  • Papouin, T. and Oliet, S. (2014). Organization, control and function of extrasinaptic NMDA receptors. Philosophical Transactions of the Royal Society B: Biological Sciences, 369 (1654), 20130601-20130601.

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