In the mammalian CNS, the principle excitatory neurotransmitter is L-Glutamate, which acts through G-protein coupled (metabotropic) receptors and ligand gated ion channels (ionotropic receptors). These receptors play a key role in excitatory synaptic plasticity and synaptic transmission, which are responsible for memory and learning.
Ionotropic Glutamate Receptors (iGluRs)
iGluRs are ligand-gated ion channels, mediating the majority of excitatory neurotransmission in the brain.
Structure of iGluRs
iGluRs are present in pre- and postsynaptic cell membranes, mainly in the CNS1. They are classified into kainate receptors, NMDA receptors and AMPA receptors. The naming of these subfamilies is based on their affinities for the synthetic agonists, kainic acid (kainate), NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)2. The delta receptor family has been categorized as an iGluR by sequence homology3 (Figure 1).
Figure 1. Diagram of the ionotropic glutamate receptor subgroups.
Similar to other ligand-gated ion channels, four domains are present in iGluRs:
- The extracellular amino-terminal domain (ATD)
- The extracellular ligand-binding domain (LBD)
- Four transmembrane domains (TMD)
- An intracellular carboxyl-terminal domain (CTD)
The second TMD (TMII) consists of a re-entrant loop that gives rise an intracellular C-terminus and an extracellular N-terminus (Figure 2).
Figure 2. Schematic structure of the ionotropic glutamate receptors. (Adapted from Traynelis, S. F. et al., 2010)
Fast excitatory neurotransmission is mediated by iGluRs. These receptors are responsible for synaptic plasticity and the capacity of humans to learn and form memories. iGluRs are nonselective cation channels, allowing ions like Ca2+, K+, or Na+ to pass through the channel when bound with glutamate1,4. An action potential (AP) is generated when a significant number of iGluRs are activated.
After the receipt of this signal, glutamate is removed from the synaptic cleft by excitatory amino acid transporters (EAATs) and as a result, the signal is effectively turned off in preparation for subsequent APs.
Excitotoxicity can occur when iGluRs are stimulated for a prolonged time as over-stimulation results in an abnormal membrane voltage potential. Glutamate uptake of EAATs is inhibited by this potential. Excitotoxicity plays a key role in nervous system injuries and neurodegenerative disorders and as a result, iGluRs become an interesting target for a number of therapeutic developments5.
References and Further Reading
- Purves, D. et al. in Neuroscience (eds. Purves, D. et al.) (Sinauer Associates, 2001)
- Alexander, S. P. H. et al. The Concise Guide to Pharmacology 2013/14: Ligand-gated ion channels. Br. J. Pharmacol. 170, 1706–1796 (2013).
- Orth, A., Tapken, D. & Hollmann, M. The delta subfamily of glutamate receptors: Characterization of receptor chimeras and mutants. Eur. J. Neurosci. 37, 1620–1630 (2013).
- Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).
- Willard, S. S. & Koochekpour, S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 9, 948–959 (2013).
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