GABA, glutamate and glutamine: the pathway in the body · Biomarker & Laboratory Analysis

This page shows the biochemical pathway behind the laboratory value GABA, glutamate, glutamine: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Glutamate and GABA are messengers of the nervous system: glutamate excites, GABA inhibits. Nerve cells make GABA from glutamate, and astrocytes resupply both via glutamine. If one side predominates, the balance of excitation and inhibition shifts.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Glutamine → Glutamate Glutaminase The enzyme glutaminase removes an amino group from glutamine, forming glutamate, the brain's main excitatory messenger. It excites the receiving cell via NMDA and AMPA receptors. Source 1, 4↕ both, depending on amount Glutamate excites the receiving cell via receptors such as NMDA and AMPA receptors, which let sodium and calcium flow in. At the same time it is the starting material for GABA and part of energy metabolism. established physiology Source 5, 2
   ⚖ When the balance tips

   too much — If glutamate stays in the cleft for a long time, the receptors stay open; in cell culture and animal models more calcium then flows into the nerve cell than it can buffer.

   too little — If little glutamate is available, excitatory transmission is weaker, and less starting material is available for making GABA.

   observed in studies · Source 5

2. Glutamate → GABA GAD65, GAD67 · Vitamin B6 (PLP) In certain nerve cells, glutamate decarboxylase (GAD65, GAD67) removes a carboxyl group from glutamate, forming GABA, the main inhibitory messenger. The enzyme needs pyridoxal phosphate, the active form of vitamin B6. GABA dampens excitation. Source 3, 2↓ depletes GABA inhibits the receiving cell: at the GABA-A receptor it opens a chloride channel, at the GABA-B receptor it acts via G proteins; the cell becomes harder to excite. In this way GABA balances glutamate. established physiology Source 2
   ⚖ When the balance tips

   too much — If a lot of GABA is present, inhibition predominates and nerve cells become harder to excite; GABA transaminase breaks down the excess in astrocytes and nerve cells.

   too little — If little PLP is available, more GAD is present as the inactive form without cofactor, and less GABA forms; inhibition is then weaker than excitation.

   observed in studies · Source 3, 2

3. GABA → Synaptic cleft · VGAT, VGLUT (vesicle) Vesicular transporters load GABA and glutamate into storage vesicles. On a signal, the cells release the contents into the gap between two nerve cells, where they bind to receptors. How long they stay there sets the signal strength. Source 1, 2↕ both, depending on amount In the cleft, excitation and inhibition meet: how long glutamate and GABA stay there determines the strength of the signal. Rapid uptake into astrocytes and nerve cells ends it. established physiology Source 1, 5
   ⚖ When the balance tips

   too much — If the messengers are cleared from the cleft more slowly, they act longer and also at neighbouring synapses; with glutamate, more calcium then flows into the cells.

   too little — If little is released, for example because the store in the vesicles is small, the signal at the receiving cell is weaker.

   observed in studies · Source 5, 1

4. In the astrocyte → Glutamine (astrocyte) Glutamine synthetase · ATP, Ammonia Glutamine synthetase adds an amino group from ammonia to glutamate, using up ATP. The astrocyte passes the glutamine back to the nerve cell, closing the cycle. At the same time ammonia is bound. Source 1, 4↑ supplies Glutamine synthetase binds ammonia that would otherwise remain free in the brain, and makes glutamate transportable without excitatory action. In the brain the enzyme is found mainly in astrocytes. established physiology Source 1, 4
   ⚖ When the balance tips

   too much — If a lot of ammonia arises, glutamine synthetase binds more of it and uses more ATP to do so; the astrocyte releases the additional glutamine.

   too little — If glutamine synthetase works more slowly, for example when little Mg-ATP is available, more glutamate and ammonia remain in the astrocyte, and the nerve cell receives less glutamine.

   observed in studies · Source 1, 7

5. In the astrocyte → Succinic semialdehyde GABA transaminase · Vitamin B6 (PLP), α-Ketoglutarate GABA transaminase transfers the amino group of GABA to α-ketoglutarate. This yields succinic semialdehyde and glutamate. This enzyme also works with pyridoxal phosphate. This ends the action of GABA. Source 4, 1↓ depletes GABA transaminase ends the action of GABA for good and recovers glutamate in the process, so the amino group is not lost. If the enzyme is inhibited, GABA rises, as the prescribing information for vigabatrin describes. established physiology Source 4, 6
   ⚖ When the balance tips

   too much — If GABA transaminase runs fast, GABA is broken down quickly, and less of it remains for inhibition.

   too little — If GABA transaminase is slowed, as described for vigabatrin, GABA is broken down more slowly and is present in the nervous system in higher amounts.

   established physiology · Source 4, 6

6. Succinic semialdehyde → Succinate SSADH · NAD⁺ Succinic semialdehyde dehydrogenase turns it into succinate, an intermediate of the citric acid cycle. Via this shunt, GABA flows back into energy metabolism. With little NAD⁺, this step runs more slowly. Source 4, 2↑ supplies Via succinate, the carbon skeleton of GABA enters the citric acid cycle and provides energy there; this loop is called the GABA shunt. NAD⁺ accepts hydrogen in the process. established physiology Source 4, 2
   ⚖ When the balance tips

   too much — If a lot of GABA drains away via the shunt, more carbon enters the citric acid cycle, and less GABA remains for signalling.

   too little — If little NAD⁺ is available, the dehydrogenase works more slowly, and succinic semialdehyde is converted to succinate more sluggishly.

   established physiology · Source 4, 2

Further stations

• Glutamine — amino acid from astrocytes Glutamine is the form in which the brain's support cells (astrocytes) resupply nerve cells. It carries no electrical charge and is easily moved across membranes. It does not act as a messenger itself. Source 1, 2↑ supplies Glutamine is the uncharged carrier that resupplies glutamate and GABA without acting as a messenger itself. At the same time it carries the nitrogen from ammonia from the astrocyte to the nerve cell. established physiology Source 1, 2
  ⚖ When the balance tips

  too much — If a lot of glutamine arrives, glutamate does not form without limit: the nerve cell's glutaminase is slowed by its own product, glutamate.

  too little — If the astrocyte supplies little glutamine, the nerve cell refills its store of glutamate and GABA only slowly, because it can hardly make either from glucose alone.

  observed in studies · Source 4, 1

• In the astrocyte — uptake via transporters Astrocytes clear glutamate from the cleft via the transporters EAAT1 and EAAT2, and GABA via GAT transporters. This ends the signal and the substance becomes available again. If the transporters work more slowly, glutamate stays in the cleft longer. Source 5, 1↓ depletes The transporters remove glutamate and GABA from the cleft and so end the signal; EAAT2 accounts for most glutamate uptake in the brain. The energy comes from the sodium gradient. established physiology Source 5, 1
  ⚖ When the balance tips

  too much — If the transporters work very fast, glutamate stays in the cleft only briefly, and the signal stays confined to the single synapse.

  too little — If the transporters work more slowly, glutamate stays in the cleft longer; in animal models without EAAT2, glutamate rises outside the cells and nerve cells become overexcited.

  observed in studies · Source 5

Cofactors in this pathway

• Vitamin B6 (PLP) — Cofactor of glutamate decarboxylase, which forms GABA, and of GABA transaminase; without PLP less GABA forms Source 3, 4In the ORY catalogue as a laboratory value: Vitamin B6
• Magnesium — Metal ion and part of Mg-ATP at the active site of glutamine synthetase; needed to bind ammonia Source 7In the ORY catalogue as a laboratory value: Magnesium
• α-Ketoglutarate — Accepts the amino group from GABA at GABA transaminase; glutamate is thus recovered Source 4, 1In the ORY catalogue as a laboratory value: Alpha-Ketoglutarat (2-Oxoglutarat)
• NAD⁺ — Accepts hydrogen when SSADH converts succinic semialdehyde to succinate; with little NAD⁺ the step slows Source 4In the ORY catalogue as a laboratory value: NAD⁺ (Nicotinamidadenindinukleotid)
• Sodium — The transporters EAAT1 and EAAT2 carry glutamate into the astrocyte together with sodium; the gradient drives uptake Source 5In the ORY catalogue as a laboratory value: Natrium (intrazellulär)
• Potassium — Moved out of the cell in exchange during glutamate transport via EAAT; this keeps uptake going Source 5In the ORY catalogue as a laboratory value: Kalium (intrazellulär)

What acts on this pathway

• Vigabatrin — Vigabatrin binds irreversibly to GABA transaminase. The prescribing information states that GABA is therefore broken down more slowly and is present in higher amounts in the nervous system. Source 6

Sources

1. Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 2006 · PubMed 16787421
2. Andersen JV, Schousboe A et al. Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission - The essential roles of astrocytes. J Neurochem 2023 · PubMed 36919769
3. Martin DL, Rimvall K. Regulation of gamma-aminobutyric acid synthesis in the brain. J Neurochem 1993 · PubMed 8419527
4. Waagepetersen HS, Sonnewald U, Schousboe A. Compartmentation of glutamine, glutamate, and GABA metabolism in neurons and astrocytes: functional implications. Neuroscientist 2003 · PubMed 14580123
5. Danbolt NC. Glutamate uptake. Prog Neurobiol 2001 · PubMed 11369436
6. US prescribing information Vigabatrin (DailyMed), section 12.1 Mechanism of Action · Prescribing information
7. Eisenberg D, Gill HS, Pfluegl GM et al. Structure-function relationships of glutamine synthetases. Biochim Biophys Acta 2000 · PubMed 10708854

Related pathways

• Alanine — glutamate
• Citric acid cycle — succinate
• Liver enzymes — Vitamin B6, Magnesium
• Branched-chain amino acids — Vitamin B6, Alpha-Ketoglutarat (2-Oxoglutarat)
• Carnitine — Vitamin B6, Alpha-Ketoglutarat (2-Oxoglutarat)

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
Legal notice Privacy policy All biomarkers