Glutamate: The Tastiest Neurotransmitter

Glutamate is one of our most important neurotransmitters, but our taste buds also utilize it to signal umami taste. Is this purely a coincidence? In this article we’ll go over the basic functions of Glutamate as well as delve into why

Mmm Glutamate… 🤤

Glutamate is the Tastiest Neurotransmitter

Function

Glutamate is the single most prolific neurotransmitter we have, and is probably one of if not the most important neurotransmitter in the body. This is due to its intimate role in allowing our nervous system to function.

Glutamate is the principle excitatory neurotransmitter, and generally induces neuronal activity rather than suppress it. Glutamate is essentially used as the “gas pedal”, in contrast to GABA’s “brake pedal”, and serves several important excitatory functions. We’ll go over the two most prominent ones today: Triggering action potentials, and Long Term Potentiation (LTP).

Action Potentials

Back in a previous article (https://www.drugnerd.net/blog/pharmacodynamics-basics-what-the-hell-is-an-agonist-or-antagonist-25gz7) we described the basic functionality of a neuron. We discussed that a core part of a neuron’s functionality involves something called an Action Potential. Once an action potential occurs, the cell undergoes a series of chemical and electrical changes which triggers neurotransmitters to be carried down the axon into the neuron’s downstream synapses (there, it might trigger another action potential in the next neuron, leading to cascading effects). Colloquially, this is what is known as a neuron “firing”.

A neuron

AMPA Receptor

In each of a neuron’s incoming synapses (at the end of its dendrites), there are numerous AMPA Receptors, and they act as the gatekeepers to determine when a cell should fire an action potential. AMPA receptors accept glutamate from the previous neuron. When the previous neuron fires an action potential, it will trigger release of neurotransmitters into the synapse, and if there were enough glutamate released from the previous cell, they will eventually find their way to an open AMPA receptor and activate it.

AMPA receptors are ionotropic receptors, meaning they act as gates for charged ions to flow through. Only when a glutamate (or any other AMPA agonist) molecule binds to the AMPA receptor will it open its gates. Depending on the subtype of AMPA receptor, it is permeable to a different subset of ions including: calcium, sodium, and potassium.

Once activated, these positively charged ions flow into the neuron. If enough of the neuron’s incoming synapses have been activated by glutamate, then enough ions would have flowed into the cell to trigger “depolarization”, meaning the cell now has less negative charge inside it than outside (due to the inflow of positive ions). Depolarization is enables an action potential to fire.

AMPA receptors only open very briefly (1ms), so a single AMPA receptor being activated is not enough to trigger a depolarization. Only if numerous AMPA receptors on numerous incoming synapses all open would the cell fire an action potential. This essentially implements a “voting system” that allows neurons to ignore potentially useless or incorrect stray signals and is part of how our brain filters out signal from noise.

https://commons.wikimedia.org/wiki/File:AMPA_receptor.png

NMDA Receptor

The second primary function of Glutamate is in facilitating neuronal learning in a process known as Long Term Potentiation (LTP).

The NMDA receptor is also an ionotropic receptor, meaning it opens a gate that lets in charged ions whenever it is activated. However, NMDA is a bit more complicated than AMPA receptor, and activating it with glutamate alone isn’t enough to allow ions to pass through.

The NMDA receptor also allows Magnesium and Zinc ions to bind to it, essentially getting stuck in the gate and “blocking” the door. This means that even when glutamate activates the NMDA receptor, ions still cant flow through the NMDA receptor’s ion channel because the receptor’s ion channel is going to be blocked by the Magnesium ions.

However, when a cell depolarizes, in addition to enabling an action potential, it also causes a shift in the cell’s overall charge and ions flow into and out of the cell through the AMPA receptor. These ion movements can dislodge the Magnesium ions from the NMDA receptors, unblocking the ion channel. If a depolarization happens within a narrow time window of a glutamate molecule binding to the NMDA receptor, it would fully open up and allow ions to flow in.

After NMDA receptor successfully allows in ions, the cell starts to undergo a series of changes that strengthens the synapse connection where the NMDA receptor was activated. This serves to strengthen commonly used neuronal circuitry over time while ignoring neuronal circuitry which are rarely used. This is a process called Long Term Potentiation and is a big part of how our brain learns and adapts to new situations.

Since the NMDA receptor requires two separate events to happen at the same time (previous neuron firing an action potential AND this neuron also firing an action potential), the receptor is essentially a “coincidence detector”. This feature of NMDA receptor enables the neuron to only strengthen synapses that are both commonly used AND consistently triggers action potentials. This essentially allows the neuron to not ignore synapses that might be commonly used but rarely triggers an action potential.

This means your brain can use this mechanism to not reinforce neurons that send a lot of useless signals.

https://en.wikipedia.org/wiki/NMDA_receptor#/media/File:Activated_NMDAR.svg

Neuroplasticity

This process is one of the core components behind neuroplasticity, and in recent years more and more research have begun to surface an intricate link between depression (as well as anxiety and PTSD) and lowered neuroplasticity. Utilizing drugs affecting the NMDA receptor, we have found some efficacy in inducing heightened neuroplasticity, which has shown some promising results in patients suffering from treatment resistant depression.

The hypothesis is that neuroplasticity allows our brains to heal and move on from traumas, and lowered neuroplasticity can be responsible for prolonged depression or anxiety. Neuroplasticity gives your brain the tools to make lasting positive changes to both your mental health and lifestyle.

Taste

For animals capable of digesting it (carnivores and omnivores), the flesh of other animals is a great source of both calories and much needed protein. Animals who have a genetic mutation that would incentivize them to seek out meat, thus, would have an evolutionary advantage compared to their competitors.

So what ended up being the solution that arose evolutionarily? Using Glutamate as a proxy to detect the presence of animal flesh. Owing to glutamate’s vital importance in allowing the nervous system to even work at all, all animals require a large amount of it for basic function. Since animal meat is filled with glutamate, having specialized taste bud that can detect glutamate provided a big competitive advantage. These taste buds signal the presence of glutamate to the brain, which evolved to interpret it as a very rewarding and pleasurable taste: umami aka savoriness.

https://en.wikipedia.org/wiki/Taste_bud#/media/File:1402_The_Tongue.jpg

MSG

The common spice Monosodium Glutamate works on the exact same principle. MSG is the salt form of Glutamate, meaning it is attached to a Sodium ion to form an ionic compound. The sodium ion contributes both stability and an added salty taste to the base compound glutamate, making it a more stable and even tastier flavor modulator than raw glutamate itself.

MSG is a common ingredient in numerous cuisines, particularly in East Asia, but is also itself found naturally in large quantities in savory foods.

MSG, a savory spice: https://en.wikipedia.org/wiki/Monosodium_glutamate#/media/File:Monosodium_glutamate_crystals.jpg