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The Glutamatergic Synapse

 

Overview

Introduction

It is commonly known that neurons communicate via synapses. At the synapse the incoming electrical signal is converted into a chemical messenger, the neurotransmitter. Upon stimulation, the neurotransmitter is released from the presynapse of the transmitting neuron into the synaptic cleft and binds to postsynaptic receptors of the receiving neuron. Neurons can be excitatory or inhibitory depending on the neurotransmitter type. Nowadays, there are more than 100 neurotransmitters known, which allows a huge diversity in chemical signaling between neurons (Purves et al., 2008).

In the mammalian central nervous system (CNS), glutamate is the predominant excitatory neurotransmitter. It is estimated that more than half of all synapses release glutamate and that almost all excitatory neurons in the CNS are glutamatergic.

 

The Glutamatergic Tripartite Synapse

Astrocytes play a very important role at the glutamatergic synapse (Hertz, 1979, Schousboe et al., 2013 & 2014), and it was Alfonso Araque (Araque et al., 1999) who described the astrocyte as being the third element of the synapse. The so called ‘tripartite synapse’ consists of the pre- and postsynaptic nerve terminal and the perisynaptic astrocytic process (PAP). The neuron and the astrocyte can be viewed as a metabolic unit (Squire et al., 2002, Benarroch 2016). In case of the glutamatergic synapse, the astrocyte fulfills at least two specially important tasks for the neuron:

  1. Uptake of glutamate from the synaptic cleft:  Excessive activation of glutamate receptors is excitotoxic for the neuron, also known as glutamate excitotoxicity. To prevent toxicity, the astrocytes take up glutamate almost immediately after neuronal release.
  2. Supply of glutamine as precursor of glutamate: The astrocyte is needed to maintain and to regulate neurotransmission at the glutamatergic nerve terminal (Perea et al., 2009), and it controls the biosynthesis and the turnover of glutamate. To this end, the astrocyte provides the neuron with the synaptically inert precursor glutamine. There are two pathways for glutamate/glutamine synthesis - de novo synthesis of glutamate/glutamine (figure 1) and recycling of glutamate/glutamine (figure 2).

Unbalanced glutamate metabolism in neurons and astrocytes is discussed to be involved in several neurological disorders (Rudy et al., 2014; Blanco-Suárez et al. 2017; Ferreira et al., 2021; Haroon & Miller 2016).

 

De novo Synthesis of Glutamate

Glutamate is a nonessential amino acid that does not cross the blood brain barrier and therefore has to be synthesized in the brain (Purves et al., 2008). De novo synthesis is possible by the citric acid cycle (TCA), which is not only a pathway to generate ATP but also provides intermediates for biosynthesis (Berg et al., 2003; Schousboe et al., 2013) (figure 1). Glutamate for example is derived from alpha-Ketoglutarate (figure 1 – step 1). Intermediates taken from the TCA for neurotransmitter biosynthesis have to be replenished immediately to ensure a continuous availability of metabolites. In mammals, oxaloacetate (OAA) is replenished by carboxylation of pyruvate catalyzed by pyruvate carboxylase (PC), an enzyme which is only expressed in astrocytes but not in neurons (figure 1 – step 2). Consequently, the neuron itself is not able to synthesize glutamate de novo (Bak et al., 2006). That implicates that the glutamatergic neuron is dependent on astrocytes to refill the glutamate pool for transmission. Because glutamate itself is excitotoxic, it is converted into glutamine by glutamine synthetase (GS) before transfer from astrocyte to neuron (figure 1 – step 3, 4). The glutamatergic neuron expresses the enzyme glutaminase 1 (GLS1), also known as PAG (phosphate-activated glutaminase) and converts glutamine back into glutamate (figure 1 – step 5).

Figure 1 (clickable products): De novo synthesis of glutamate takes place in astrocytes.

(1) Glutamate (Glu) can be built from alpha-Ketoglutarate (alpha-KG), an intermediate of the citric acid cycle (TCA cycle). The enzymes glutamate dehydrogenase (GDH) and aspartate aminotransferase (AAT) catalyze the reversible reaction of alpha-KG to glutamate. (2) The pyruvate carboxylase (PC) is only expressed in astrocytes and carboxylates pyruvate to oxaloacetate (OAA) to replenish the TCA cycle intermediates. (3) Glutamate is converted into glutamine (Gln) by glutamine synthetase (GS). (4) Glutamine is transferred into the neuron. (5) In the neuron, glutamine is converted back into glutamate by the enzyme glutaminase 1 (GLS1).

 

The Glutamate-Glutamine Cycle

Interestingly, the main part of glutamine is not built by de novo synthesis. The quantitative predominant metabolic pathway is the glutamate-glutamine cycle (figure 2), also known as glutamate-glutamine shuttle. This cycle is one example of the cooperation between neurons and astrocytes and describes the recycling of glutamate for neurotransmission. After release, glutamate binds to glutamate receptors located primarily in the postsynaptic membrane (figure 2 - step 1). There are two different types of glutamate receptors, ionotrophic receptors (AMPAR/GluA, KainateR/GluK, NMDAR/GluN receptors) and G-protein coupled metabotropic receptors (mGluRs). To prevent glutamate excitotoxicity caused by excessive activation of glutamate receptors, the astrocyte takes up glutamate almost immediately after its release via excitatory amino acid transporters (EAATs) (Malik & Willnow 2019), mostly by EAAT 1 (also known as GLAST - glutamate-aspartate transporter) and EAAT 2 (also known as GLT1 -glutamate transporter 1) (figure 2 - step 2). A minor part of glutamate is taken up by the neurons over EAAT 3 (also known as EAAC1 - excitatory amino acid carrier 1). The astrocyte converts the main part of glutamate into glutamine, catalyzed by glutamine synthetase (GS) (figure 2 - step 3). Glutamine is shuttled to the neuron via sodium-coupled neutral amino acid transporters (SNATs) (figure 2 - step 4). In the mitochondria of the neuron glutamine is deaminased to glutamate by the glutaminase 1 (GLS1) (figure 2 - step 5). The recycled glutamate is transferred into synaptic vesicles by vesiculary glutamate transporters (VGLUTs) and is prepared for the next round of transmission (figure 2 - step 6).

Figure 2 (clickable products): Glutamate-glutamine cycle between the glutamatergic neuron and the astrocyte.

(1) Glutamate (Glu) is released and binds to ionotrophic and metabotropic receptors (AMPAR/GluAKainateR/GluKNMDAR/GluN, mGluRs). (2) Glutamate is taken up mainly by the astrocytes via excitatory amino acid transporters EAAT 1/2 and partially by the neurons via EAAT 3. (3) The astrocytic glutamine synthetase converts glutamate (Glu) into glutamine (Gln). (4) Synaptically inert glutamine is transferred from the astrocyte to the neuron. (5) Glutamine (Gln) is converted back into glutamate (Glu) by the mitochondrial glutaminase 1 (GLS1). (6) Glutamate is translocated into vesicles by the vesiculary glutamate transporters (VGLUTs) and is ready for the next round of transmission.

 

Products

Products AMPAR/GluA
Cat. No. Product Description Application Quantity Price Cart
182 403GluA, rabbit, polyclonal, affinity purifiedaffinity WB IHC EM 50 µg$370.00
182 408GluA, rabbit, monoclonal, recombinant IgGrecombinant IgGICC 50 µg$415.00
182 411GluA, mouse, monoclonal, purified IgG IgGICC 100 µg$415.00
182 411C3GluA, mouse, monoclonal, purified IgG IgG, Oyster 550ICC 100 µg$465.00
182 003GluA1, rabbit, polyclonal, affinity purifiedaffinity K.O.WB IP ICC 50 µg$370.00
182 011GluA1, mouse, monoclonal, purified IgG IgG K.O.WB IP ICC IHC IHC-P 100 µg$425.00
182-01PGluA1, control peptidecontrol peptide100 µg$90.00
182-0PGluA1, control proteincontrol protein100 µg$90.00
182 103GluA2, rabbit, polyclonal, affinity purifiedaffinity WB IP ICC IHC ExM 50 µg$370.00
182 105GluA2, Guinea pig, polyclonal, affinity purifiedaffinity WB ICC IHC IHC-P 50 µg$450.00
182 111GluA2, mouse, monoclonal, purified IgG IgGWB IP Clarity 100 µg$415.00
182 113GluA2, rabbit, polyclonal, affinity purifiedaffinity WB IP 50 µg$370.00
182 211GluA2, mouse, monoclonal, purified IgM IgMWB 100 µg$415.00
182-1PGluA2, control proteincontrol protein100 µg$90.00
182 203GluA3, rabbit, polyclonal, affinity purifiedaffinity WB IP 50 µg$370.00
Result count: 18
Products EAAT
Cat. No. Product Description Application Quantity Price Cart
250 103EAAT 1, rabbit, polyclonal, affinity purifiedaffinity K.O.
extracellular domain
WB 50 µg$370.00
250 113EAAT 1, rabbit, polyclonal, affinity purifiedaffinity K.O.
cytoplasmic domain
WB IP ICC IHC 50 µg$370.00
250 114EAAT 1, Guinea pig, polyclonal, antiserumantiserum
cytoplasmic domain
WB ICC IHC IHC-P 100 µl$350.00
250 116EAAT 1, chicken, polyclonal, IgY fractionIgY fraction
cytoplasmic domain
WB ICC IHC 200 µl$350.00
250-11PEAAT 1, control peptidecontrol peptide
cytoplasmic domain
100 µg$90.00
250-1PEAAT 1, control peptidecontrol peptide
extracellular domain
100 µg$90.00
250 203EAAT 2, rabbit, polyclonal, affinity purifiedaffinity K.O.
extracellular domain
WB IHC IHC-P 50 µg$370.00
250 204EAAT 2, Guinea pig, polyclonal, antiserumantiserum K.O.
extracellular domain
WB ICC IHC IHC-P 100 µl$350.00
250-2PEAAT 2, control peptidecontrol peptide
extracellular domain
100 µg$90.00
250 303EAAT 3, rabbit, polyclonal, affinity purifiedaffinity
cytoplasmic domain
ICC IHC 50 µg$370.00
250 313EAAT 3, rabbit, polyclonal, affinity purifiedaffinity
cytoplasmic domain
WB 50 µg$370.00
250-31PEAAT 3, control peptidecontrol peptide
cytoplasmic domain
100 µg$90.00
Result count: 12
Products Glutaminase 1
Cat. No. Product Description Application Quantity Price Cart
456 003Glutaminase 1, rabbit, polyclonal, affinity purifiedaffinity WB ICC IHC 50 µg$370.00
456 004Glutaminase 1, Guinea pig, polyclonal, antiserumantiserumWB ICC IHC 100 µl$350.00
456-0PGlutaminase 1, control peptidecontrol peptide100 µg$90.00
Result count: 3
Products Glutamine Synthetase
Cat. No. Product Description Application Quantity Price Cart
367 004Glutamine synthetase, Guinea pig, polyclonal, antiserumantiserumWB IHC 100 µl$350.00
367 005Glutamine synthetase, Guinea pig, polyclonal, affinity purifiedaffinity WB IHC IHC-P 50 µg$450.00
367 011Glutamine synthetase, mouse, monoclonal, purified IgG IgGWB IHC IHC-P 100 µg$415.00
Result count: 3
Products KainateR/GluK
Cat. No. Product Description Application Quantity Price Cart
180 313GluK 1, rabbit, polyclonal, affinity purifiedaffinity IHC 50 µg$370.00
180 003GluK 2, rabbit, polyclonal, affinity purifiedaffinity WB 50 µg$370.00
180-0PGluK 2, control proteincontrol protein100 µg$90.00
180 203GluK 3, rabbit, polyclonal, affinity purifiedaffinity WB IHC 50 µg$370.00
180 103GluK 5, rabbit, polyclonal, affinity purifiedaffinity WB IHC 50 µg$370.00
180-1PGluK 5, control proteincontrol protein100 µg$90.00
Result count: 6
Products mGluR
Cat. No. Product Description Application Quantity Price Cart
191 002mGluR1-α, rabbit, polyclonal, antiserumantiserumWB 200 µl$350.00
191-0PmGluR1-α, control proteincontrol protein100 µg$90.00
191 103mGluR2, rabbit, polyclonal, affinity purifiedaffinity WB 50 µg$370.00
191-1PmGluR2, control peptidecontrol peptide100 µg$90.00
191 203mGluR7, rabbit, polyclonal, affinity purifiedaffinity WB ICC 50 µg$370.00
Result count: 5
Products NMDAR/GluN
Cat. No. Product Description Application Quantity Price Cart
114 003GluN 1, rabbit, polyclonal, affinity purifiedaffinity WB IP ELISA 50 µg$370.00
114 011GluN 1, mouse, monoclonal, purified IgG IgG K.O.WB IP ICC IHC IHC-P ExM ELISA 100 µg$425.00
114 103GluN 1, rabbit, polyclonal, affinity purifiedaffinity ICC IHC 50 µg$370.00
114-0PGluN 1, control peptidecontrol peptide100 µg$90.00
244 002GluN 2 A/B, rabbit, polyclonal, antiserumantiserumWB IP 200 µl$350.00
244 003GluN 2 A/B, rabbit, polyclonal, affinity purifiedaffinity WB IP ICC 50 µg$450.00
244 004GluN 2 A/B, Guinea pig, polyclonal, antiserumantiserumWB 100 µl$350.00
244-0PGluN 2 A/B, control peptidecontrol peptide100 µg$90.00
244 103GluN 2 B, rabbit, polyclonal, affinity purifiedaffinity WB IP 50 µg$370.00
244 115GluN 2 B, Guinea pig, polyclonal, affinity purifiedaffinity WB 50 µg$450.00
244-1PGluN 2 B, control peptidecontrol peptide100 µg$90.00
Result count: 11
Products VGLUT
Cat. No. Product Description Application Quantity Price Cart
135 011VGLUT 1, mouse, monoclonal, purified IgG IgG K.O.WB IP ICC IHC IHC-P 100 µg$415.00
135 011BTVGLUT 1, mouse, monoclonal, purified IgG IgG, biotin K.O.WB ICC IHC IHC-P 100 µg$465.00
135 011C3VGLUT 1, mouse, monoclonal, purified IgG IgG, Sulfo-Cyanine 3 K.O.ICC IHC 100 µg$465.00
135 011C5VGLUT 1, mouse, monoclonal, purified IgG IgG, Sulfo-Cyanine 5 K.O.ICC IHC 100 µg$465.00
135 302VGLUT 1, rabbit, polyclonal, antiserumantiserum K.O.WB IP ICC IHC IHC-P 200 µl$350.00
135 303VGLUT 1, rabbit, polyclonal, affinity purifiedaffinity K.O. K.D.WB IP ICC IHC IHC-P EM ELISA 50 µg$450.00
135 303C3VGLUT 1, rabbit, polyclonal, affinity purifiedaffinity , Sulfo-Cyanine 3 K.O.ICC IHC 50 µg$475.00
135 303C5VGLUT 1, rabbit, polyclonal, affinity purifiedaffinity , Oyster 650 K.O.ICC IHC 50 µg$475.00
135 304VGLUT 1, Guinea pig, polyclonal, antiserumantiserum K.O.WB IP ICC IHC IHC-P ExM Clarity EM FACS 100 µl$375.00
135 307VGLUT 1, goat, polyclonal, antiserumantiserum K.O.WB IP ICC IHC 200 µl$330.00
135 308VGLUT 1, rabbit, monoclonal, recombinant IgGrecombinant IgG K.O.WB IP ICC IHC IHC-P 50 µg$415.00
135 311VGLUT 1, mouse, monoclonal, purified IgG IgG K.O.WB IP ICC IHC IHC-P ELISA 100 µg$415.00
135 316VGLUT 1, chicken, polyclonal, IgY fractionIgY fraction K.O.WB ICC IHC IHC-P IHC-Fr 200 µl$350.00
135 318VGLUT 1, Guinea pig, monoclonal, recombinant IgGrecombinant IgG K.O.WB ICC IHC IHC-P 50 µg$415.00
135 511VGLUT 1, mouse, monoclonal, purified IgG IgG K.O.IP ICC IHC IHC-P 100 µg$415.00
Result count: 39
 

Author: Dr. Liane Wüstefeld

Head of Histology Department with main emphasis in neuroscience. As an expert for histology, Liane validates our in-house developed antibodies for the immunohistochemistry (IHC) application.

 

Literature

Araque et al., 1999: Tripartite synapses: glia, the unacknowledged partner. PMID: 10322493

Bak et al., 2006: The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. PMID: 16787421

Benarroch 2016: Astrocyte signaling and synaptic homeostasis. PMID: 27335113

Blanco-Suárez et al. 2017: Role of astrocyte–synapse interactions in CNS disorders. PMID: 27381164

Ferreira et al., 2021: Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices. PMID: 33492574

Haroon & Miller 2016: Inflammation Effects on Brain Glutamate in Depression: Mechanistic Considerations and Treatment Implications. PMID: 27830574

Hertz, 1979: Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino acid transmitters. PMID: 42117

Malik & Willnow 2019: Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. PMID: 31726793

Perea et al., 2009: Tripartite synapses: astrocytes process and control synaptic information. PMID: 19615761

Rudy et al., 2014: The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease. PMID: 25821641

Schousboe et al., 2013: Astrocytic Control of Biosynthesis and Turnover of the Neurotransmitters Glutamate and GABA. PMID: 23966981

Schousboe et al., 2014: Glutamate Metabolism in the Brain Focusing on Astrocytes. PMID: 25236722

Squire et al., 2002: Fundamental Neuroscience, 2nd Edition, ISBN: 9780080521800

Purves et al., 2008: Neuroscience, 4th Edition, ISBN: 9780878936977

Berg et al., 2002: Biochemistry, 5th Edition, ISBN: 9780716746843