Glutamate as a Neurotransmitter

Abstract

Glutamate is an amino acid used in biochemical pathways of all cells, but it is also packaged and released as a neurotransmitter from many neurons in the vertebrate central nervous system (CNS). Glutamate is released at specific junctions, synapses, between a glutamate‐releasing neuron and target neurons that express surface receptors for glutamate. Most neurons in the vertebrate CNS, even if they themselves do not use glutamate as a neurotransmitter, have glutamate receptors. Glutamate receptors initiate electrical and biochemical signals in the target cell and can induce changes in strength of signalling that neuroscientists believe underlie the ability of thoughts and behaviours to change with experience. Glutamate receptors fall into two classes: ligand‐gated ion channels (ionotropic) and G protein coupled (metabotropic). In addition to propagating and modulating normal electrical signalling, glutamate receptors, activated excessively, can cause neurotoxicity in disease states.

Key Concepts

  • Glutamate is used as a neurotransmitter at the majority of synapses in the vertebrate CNS.
  • Glutamate typically has an excitatory action on target neurons, increasing the probability of electrical impulse firing in the target.
  • Glutamate acts through G protein‐coupled receptors and through ligand‐gated ion channels.
  • Glutamate synapses exhibit remarkable plasticity (malleability) that may play an important role in memory formation.
  • In excess glutamate can be neurotoxic, acting through the same glutamate receptors that mediate normal signalling.

Keywords: excitatory; spine; excitotoxicity; NMDA; long‐term potentiation

Figure 1. The site of glutamate synapses is typically on dendritic spines. (a) A typical neuron with dendrites (receiving part of the neuron) near the cell body, a long axon (the sending branch of the neuron), and axon terminals, where transmitter is released. The red box indicates a dendrite segment which, in some neuronal types, will contain dendritic spines (magnified in panel b) are located. Spines exhibit varied shapes but are typical recipients of glutamate synapses (panel c). The presynaptic axon terminal in panel c contains vesicles filled with glutamate. The postsynaptic spine contains recipient receptors. Astrocytes nearby are responsible for the bulk of glutamate removal following synaptic release and receptor activation.
Figure 2. Glutamate receptors. (a) Cartoon structures of ionotropic (iGluRs) and metabotropic (G protein‐coupled; mGluRs) receptors. Different receptor domains are indicated: Amino terminal domain (ATD), ligand‐binding domain (LBD), transmembrane domain (TMD), C‐terminal domain (CTD), and cysteine‐rich domain (CTD). Also shown are allosteric modulators (ligands that bind at sites distinct from the transmitter), which can influence receptor activation positively or negatively for therapeutic or experimental purposes. Channel blockers are drugs that occlude ion flow through the channel of ionotropic channels. (b) Responsiveness of various receptors to varied concentrations of glutamate, and the typical physiological concentrations of glutamate achieved in various cellular and extracellular compartments. Reiner, A., & Levitz, J. . Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert. Neuron, 98(6), 1080–1098. doi:10.1016/j.neuron.2018.05.018. © 2018 Elsevier.
close

References

Bear MF, Kleinschmidt A, Gu Q and Singer W (1990) Disruption of experience‐dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist. The Journal of Neuroscience 10: 909–925.

Bliss TVP and Lomo T (1973) Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. Journal of Physiology (London) 232: 331–356.

Castillo PE, Malenka RC and Nicoll RA (1997) Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388 (6638): 182–186.

Danbolt NC (2001) Glutamate uptake. Progress in Neurobiology 65: 1–105.

Greger IH and Mayer ML (2019) Structural biology of glutamate receptor ion channels: towards an understanding of mechanism. Current Opinion in Structural Biology 57: 185–195.

Hebb DO (1949) The Organization of Behavior: A Neuropsychological Theory. Wiley; Chapman & Hall: New York.

Huettner JE (2003) Kainate receptors and synaptic transmission. Progress in Neurobiology 70: 387–407.

Malenka RC and Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44: 5–21.

Malik AR and Willnow TE (2019) Exitatory amino acid transporters in physiology and disorders of the central nervous system. International Journal of Molecular Sciences 20 (22): 5671.

Mayer ML, Westbrook GL and Guthrie PB (1984) Voltage‐dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309: 261–263.

Megias M, Emri Z, Freund TF and Gulyas AI (2001) Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102: 527–540.

Monteiro P and Feng G (2017) SHANK proteins: roles at the synapse and in autism spectrum disorder. Nature Reviews Neuroscience 18: 147–157.

Niswender CM and Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual Review of Pharmacology and Toxicology 50: 295–322.

Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721.

Omote H, Miyaji T, Juge N and Moriyama Y (2011) Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50: 5558–5565.

Reiner A and Levitz J (2018) Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98: 1080–1098.

Rodríguez‐Moreno A and Lerma J (1998) Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20 (6): 1211–1218.

Rothman SM and Olney JW (1987) Excitotoxicity and the NMDA receptor. Trends in Neurosciences 10: 299–302.

Schell MJ, Molliver ME and Snyder SH (1995) D‐serine, and endogenous synaptic modulator: localization to astrocytes and glutamate‐stimulated release. Proceedings of the National Academy of Scienceof the United States of America 92 (9): 3948–3952.

Sobolevsky AI, Rosconi MP and Gouaux E (2009) X‐ray structure, symmetry and mechanism of an AMPA‐subtype glutamate receptor. Nature 462: 745–756.

Sonnewald U and Schousboe A (2016) Introduction to the glutamate‐glutamine cycle. In: Sonnewald U and Schousboe A (eds) The Glutamate/GABA‐Glutamine Cycle, Advances in Neurobiology, vol. 13, pp 1–7.

Stansley BJ and Conn PJ (2019) Neuropharmacological insight from allosteric modulation of mGlu receptors. Trends in Pharmacological Sciences 40 (4): 240–252.

Traynelis SF, Wollmuth LP, McBain CJ, et al. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacological Reviews 62: 405–496.

Trudeau LE and EI Mestikawy S (2018) Glutamate cotransmission in cholinergic, GABAergic and monoamine systems: contrasts and commonalities. Front Neural Circuits 12: 113.

Verpelli C, Schmeisser MJ, Sala C and Boeckers TM (2012) Scaffold proteins at the postsynaptic density. In: Kreutz M and Sala C (eds) Synaptic Plasticity, Advances in Experimental Medicine and Biology, vol. 970, pp 29–61.

Weiss J, Goldberg MP and Choi DW (1986) Ketamine protects cultured neocortical neurons from hypoxic injury. Brain Research 380 (1): 186–190.

Zorumski CF and Olney JW (1993) Excitotoxic neuronal damage and neuropsychiatric disorders. Pharmacology and Therapeutics 59: 145–162.

Further Reading

Berardi N, Pizzorusso T, Ratto GM and Maffei L (2003) Molecular basis of plasticity in the visual cortex. Trends in Neurosciences 26: 369–378.

Bliss TVP and Collingridge GL (2019) Persistent memories of long‐term potentiation and the N‐methyl‐d‐aspartate receptor. Brain and Neuroscience Advances 3: 1–10.

Chaudhry FA, Boulland JL, Jenstad M, Bredahl MK and Edwards RH (2008) Pharmacology of neurotransmitter transport into secretory vesicles. In: Handbook of Experimental Pharmacology, vol. 184, pp 77–106. Springer‐Verlag: Berlin Heidelberg

Collingridge GL and Bliss TV (1995) Memories of NMDA receptors and LTP. Trends in Neurosciences 18 (2): 54–56.

El Mestikawy S, Wallen‐Mackenzie A, Fortin GM, et al. (2011) From glutamate co‐release to vesicular synergy: vesicular glutamate transporters. Nature Reviews Neuroscience 12: 204–216.

Hardingham GE and Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews Neuroscience 11: 682–696.

Kessels HW and Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61: 340–350.

Kumar J and Mayer ML (2013) Functional insights from glutamate receptor ion channel structures. Annual Review of Physiology 75: 313–337.

Lisman JE, Raghavachari S and Tsien RW (2007) The sequence of events that underlie quantal transmission at central glutamatergic synapses. Nature Reviews Neuroscience 8: 597–609.

Nimchinsky EA, Sabatini BL and Svoboda K (2002) Structure and function of dendritic spines. Annual Review of Physiology 64: 313–353.

Yuste R (2011) Dendritic spines and distributed circuits. Neuron 71: 772–781.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lambert, Peter, and Mennerick, Steven(Aug 2020) Glutamate as a Neurotransmitter. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029140]