September 6th, 2022
Written by: Margaret Gardner
Glutamate is a busy molecule, as you may have learned from our recent post. It has many important jobs in the brain, such as sending excitatory signals between neurons and helping glia (the brain’s support cells) grow and adapt. This week, we’re taking a closer look at some of glutamate’s less commonly known (and tastier) functions – so buckle up and prepare to take your glutamate knowledge to the periphery and beyond!
The process of making, packaging, and recycling the glutamate that’s released from a neuron costs the brain lots of energy1. Luckily, cells have several ways of using glutamate to make more2.
Usually, cells get energy by converting the sugar you eat to ATP (the molecular batteries that power cells) in two steps: one inefficient step that makes a few ATP, followed by a very efficient step that takes the leftover molecules and makes a lot of ATP3. One way to think about this is like picking apples from a tree. Say you’re hungry but only want a couple apples for now, so you grab the ones that are easy-to-reach (literally, “low-hanging fruit”). However, there are a lot more apples up in the higher branches that you don’t want to waste, so you come back the next day with a ladder to pick the rest and use them to make apple sauce. At first, you only needed a little immediate energy, so you take a few apples (or produced the ATP from sugar) that were easy to get – but since there are still a lot of apples on the tree (or energy left in the sugar molecule) you’ll need to go back and finish getting them.
In neurons, that quick first quick step is linked directly to glutamate production, so that as neurons are using energy to package glutamate for release, they are simultaneously replacing it with new ATP from sugar3. Meanwhile, the supporting glia cells that take in this glutamate can make energy without needing any sugar at all 2,4. After use some energy to get the glutamate into the cell, glia can use glutamate in the second step of energy production instead of sugar, where it is broken down to make 20x the ATP it cost to take in2,4.
Even before birth, glutamate signaling has a crucial role to play in brain development, helping neurons direct each other where to go and how to organize. In embryonic and young mice, glutamate signals appear to help young neurons “migrate” by leading them to their final locations in the brain5. Activating glutamate receptors can also signal some neurons to grow toward each other and form new signaling connections6.
Glia cells also follow glutamate signals, particularly in forming, keeping and adapting myelin, the glia cells that insulate nerves to make them faster and more efficient. Glutamate signals help make immature myelin cells more mobile, so they can reach neurons that need myelinating, and trigger them to grow around these active neurons5. Signaling for more or less myelin is one way glutamate actively adapts the brain to prioritize important, frequently used connections5.
Many different cells, including types of glia and white blood cells, are involved in neuroinflammation, the immune system’s response to injury or disease in the brain7. These cells have a variety of glutamate receptors which, depending on the type, either promote or reduce inflammation when activated7. As in the rest of the body, inflammation can be useful to fight infection but can lead to tissue damage if it’s too strong or goes on too long. Long-term neuroinflammation is involved in stroke, MS, Parkinson’s, Alzheimer’s, depression, and schizophrenia7,8. Since glutamate can either increase or reduce inflammation in the brain, changes in glutamate signaling could be causing neuroinflammation in these diseases7.
Glutamate can also be converted into another molecule that helps clean up metabolic byproducts called reactive oxygen species9,10. Like leftover eggshells from making an omelet, your brain isn’t trying to make reactive oxygen species but can’t avoid it; therefore, your brain needs to discard these harmful byproducts, just like you have to toss your eggshells or else your kitchen will smell. If not neutralized by glutamate, these reactive oxygen species can impede many cellular processes, destroy important molecules, and lead to inflammation8,10.
In the body, neurons outside the brain and spinal cord – in what scientists call the peripheral nervous system – and other types of cells all run on glutamate. Many of glutamate’s functions in the periphery are similar to those it plays in the brain. For example, glutamate protects immune cells from destruction and coordinates the inflammatory response (see Figure 1)5. As for energy metabolism, glutamate breakdown following meals triggers the pancreas to release insulin, regulating blood sugar (Figure 1)9. It is also used by peripheral nerves to transmit pain signals (Figure 1)11.
Finally, the glutamate in food acts on receptors in the body. Glutamate activates a pair of receptors in the tongue that together create the savory taste of umami (Figure 1)9,12. You can stimulate these receptors with the help of monosodium glutamate, more often known as MSG, which has gained infamy and popularity since its isolation from seaweed in the late 1800s13 (though personally I do not recommend eating it straight). Glutamate next triggers receptors in the gut that promote digestion and stimulates the muscles that push food through the digestive tract, before being broken down with the rest of your meal (Figure 1)9.
As you now know, glutamate is a true renaissance molecule, relevant to a huge range of functions. With this complexity comes risk, since any problems – or attempts to treat them – can have ripple effects throughout the brain and body. Luckily, many scientists have already begun mapping the glutamate web. From the ketogenic diet to seasoning blends, the power of glutamate is already being used to improve our lives better in ways big and small.
1. Rothman DL, Behar KL, Hyder F, Shulman RG. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol. 2003;65:401-427. doi:10.1146/ANNUREV.PHYSIOL.65.092101.142131
2. Bordone MP, Salman MM, Titus HE, et al. The energetic brain – A review from students to students. J Neurochem. 2019;151(2):139-165. doi:10.1111/JNC.14829
3. Hertz L, Chen Y. Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate. Front Integr Neurosci. 2017;11. doi:10.3389/FNINT.2017.00018
4. McKenna MC. Glutamate Pays Its Own Way in Astrocytes. Front Endocrinol (Lausanne). 2013;4(DEC). doi:10.3389/FENDO.2013.00191
5. Spitzer S, Volbracht K, Lundgaard I, Káradóttir RT. Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease. Neuropharmacology. 2016;110(Pt B):574-585. doi:10.1016/J.NEUROPHARM.2016.06.014
6. Manent JB, Demarque M, Jorquera I, et al. A Noncanonical Release of GABA and Glutamate Modulates Neuronal Migration. The Journal of Neuroscience. 2005;25(19):4755. doi:10.1523/JNEUROSCI.0553-05.2005
7. Fazio F, Ulivieri M, Volpi C, Gargaro M, Fallarino F. Targeting metabotropic glutamate receptors for the treatment of neuroinflammation. Curr Opin Pharmacol. 2018;38:16-23. doi:10.1016/J.COPH.2018.01.010
8. Behl T, Makkar R, Sehgal A, et al. Current Trends in Neurodegeneration: Cross Talks between Oxidative Stress, Cell Death, and Inflammation. Int J Mol Sci. 2021;22(14). doi:10.3390/IJMS22147432
9. Brosnan JT, Brosnan ME. Glutamate: a truly functional amino acid. Amino Acids. 2013;45(3):413-418. doi:10.1007/S00726-012-1280-4
10. Hussain T, Tan B, Yin Y, Blachier F, Tossou MCB, Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev. 2016;2016. doi:10.1155/2016/7432797
11. Pankevich DE, Davis M, Altevogt BM. GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT FOR DISORDERS OF THE NERVOUS SYSTEM WORKSHOP SUMMARY Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy. The National Academies Press; 2011. Accessed June 23, 2022. http://www.nap.edu.
12. Tapiero H, Mathé G, Couvreur P, Tew KD. II. Glutamine and glutamate. Biomed Pharmacother. 2002;56(9):446-457. doi:10.1016/S0753-3322(02)00285-8
13. Eid T, Gruenbaum SE, Dhaher R, Lee TSW, Zhou Y, Danbolt NC. The glutamate-glutamine cycle in epilepsy. In: The Glutamate/GABA-Glutamine Cycle. Vol 13. Springer Science and Business Media, LLC; 2016:351-400. doi:10.1007/978-3-319-45096-4_14/FIGURES/5