Ionotropic glutamate receptors

​Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission within the brain.


Structure

iGluRs are found on pre- and postsynaptic cell membranes, primarily within the CNS1 and are divided into AMPA receptors, NMDA receptors and kainate receptors. These subfamilies are named according to their affinities for the synthetic agonists, AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), NMDA (N-methyl-d-aspartate) and kainic acid (kainate)2. The delta receptor family has been classified as an iGluR by sequence homology3. 

Similar to other ligand-gated ion channels, iGluRs are composed of four domains: the extracellular amino-terminal domain (ATD), the extracellular ligand-binding domain (LBD), four transmembrane domains (TMD), and an intracellular carboxyl-terminal domain (CTD). At the second TMD (TMII), there is a re-entrant loop that gives rise to an extracellular N-terminus and an intracellular C-terminus (Figure 1).

iGluRs are ligand-gated ion channels, found on pre- and postsynaptic cell membranes, primarily within the CNS [1]. iGluRs are divided into AMPA receptors, NMDA receptors and kainate receptors. These subfamilies are named according to their affinities for the synthetic agonists, AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), NMDA (N-methyl-d-aspartate) and kainic acid (kainate) [2]. The delta receptor family has been classified as an iGluR by sequence homology [3]. 
Similar to other ligand-gated ion channels, iGluRs are composed of four domains: the extracellular amino-terminal domain (ATD), the extracellular ligand-binding domain (LBD), four transmembrane domains (TMD), and an intracellular carboxyl-terminal domain (CTD). At the second TMD (TMII), there is a reentrant loop that gives rise to an extracellular N-terminus and an intracellular C-terminus [4] (Figure 1).

​Figure 1. Schematic structure of the ionotropic glutamate receptors. (Adapted from Traynelis, S. F. et al., 2010)


Function

iGluRs mediate fast excitatory neurotransmission and are involved in synaptic plasticity and our capacity to learn and form memories. As nonselective cation channels, iGluRs allow ions like Na+, K+ or Ca2+ to pass through the channel upon binding with glutamate1,4. Activation of a significant number of iGluRs generates an action potential (AP). After this signal is received, excitatory amino acid transporters (EAATs) remove glutamate from the synaptic cleft, effectively turning off the signal in preparation for subsequent APs.

Prolonged stimulation of iGluRs can result in excitotoxicity as over-stimulation causes an abnormal membrane voltage potential that inhibits glutamate uptake by EAATs. Excitotoxicity is a major contributor to neurodegenerative disorders and nervous system injuries, making iGluRs an interesting target for various therapeutic developments5. 

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AMPA receptors

​​AMPA receptors are co-expressed with NMDA receptors at most glutamatergic synapses in glia and neurons, and mediate the majority of fast excitatory neurotransmission within the CNS6. The modulation of AMPA receptors is also a primary mechanism of synaptic plasticity: increasing the number of AMPA receptors at the postsynaptic site can increase the response to an action potential7,8. 

The Ca2+-permeability of AMPA receptors is dictated by the GluA2 subunit. Normally impermeable to Ca2+, post-transcriptional editing of GluA2 at the TMII region (the Q/R editing site) can convert glutamine (Q) to arginine (R), rendering the receptor Ca2+-permeable4. 

GluA2 proteins throughout the CNS are almost exclusively in the calcium-impermeable state. This is important because Ca2+ entry through AMPA receptors can trigger neuronal death and can contribute to the pathogenesis of diseases like amyotrophic lateral sclerosis (ALS)9. The distribution of Ca2+-permeable and impermeable AMPA receptors therefore serves as an indicator of selective neuronal vulnerability.

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NMDA receptors

​NMDA receptors require the co-binding of glycine in addition to glutamate for activation. A glycine binding site is provided by the GluN1 and GluN3 subunits10. These receptors allow the flow of Ca2+, in addition to Na+ and K+.

Mg2+ normally blocks the NMDA channel, meaning weak stimuli triggering glutamate-binding result in only limited Ca2+ conductance1,11. In these instances, AMPA receptors mediate the excitatory postsynaptic potential through conductance of Na+ and K+. In the presence of strong stimuli, AMPA receptors depolarize the membrane enough to dislodge Mg2+ from the NMDA receptor channel. This allows NMDA receptors to respond to glutamate-binding and permit the flow of large amounts of Ca2+, Na+ and K+ through the channel. NMDA receptors therefore function as molecular coincidence detectors, requiring both glutamate binding and a strong depolarizing stimulus12.

The amount of Ca2+ entering the cell, as modulated by NMDA receptors, affects an array of local signal transduction complexes: Ca2+ can act as a secondary messenger in several signaling cascades. For example, activation of calcium/calmodulin-dependent kinase II (CaMKII), upregulation of AMPA receptor expression at the synaptic membrane, and subsequent phosphorylation of the GluA2 AMPA receptor subunit, can result in synaptic enhancement and long-term potentiation5.

Since NMDA receptors are present on both excitatory and inhibitory neurons, excessive activation can lead to excitotoxicity and neuronal death (as seen in Huntingdon’s disease), or a reduced activity that disturbs the balance of excitation/inhibition (as seen in schizophrenia)13.

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Kainate receptors

Traditionally, kainate receptors have been grouped with AMPA receptors as non-NMDA receptors, sharing many similar agonists and antagonists, but are now known to be a separate group14. 

Kainate receptors require extracellular Na+ and Cl- for their activation15,16. They are found throughout the CNS where they are usually co-expressed with AMPA and NMDA receptors, although in some regions such as the retina for example, they exist independently. Unlike AMPA and NMDA receptors, kainate receptors can also signal through G-proteins, behaving like metabotropic receptors: canonical signaling (ionotropic) is responsible for membrane depolarization, postsynaptic responses, and neurotransmitter release; while non-canonical (metabotropic) signaling activates G-proteins to affect membrane excitability, neuronal and circuit maturation, and neurotransmitter release17.

Postsynaptically, kainate receptors work much like AMPA and NMDA receptors, propagating the excitatory postsynaptic current. Presynaptically, they modulate the release of neurotransmitters at both excitatory and inhibitory synapses14. Kainate receptors also play a critical role in synaptic plasticity and are linked to a number of neurological diseases such as epilepsy, schizophrenia, and autism, yet their involvement in brain pathologies remain unclear17.

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    ​​References

    • 1.           Purves, D. et al. in Neuroscience (eds. Purves, D. et al.) (Sinauer Associates, 2001).

      2.           Alexander, S. P. H. et al. The Concise Guide to Pharmacology 2013/14: Ligand-gated ion channels. Br. J. Pharmacol. 170, 1706–1796 (2013).

      3.           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).

      4.           Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

      5.           Willard, S. S. & Koochekpour, S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 9, 948–959 (2013).

      6.           Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

      7.           Ju, W. et al. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors. Nat. Neurosci. 7, 244–53 (2004).

      8.           Derkach, V. A., Oh, M. C., Guire, E. S. & Soderling, T. R. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat. Rev. Neurosci. 8, 101–13 (2007).

      9.           Van Den Bosch, L., Vandenberghe, W., Klaassen, H., Van Houtte, E. & Robberecht, W. Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons. J. Neurol. Sci. 180, 29–34 (2000).

      10.        Yao, Y., Belcher, J., Berger, A. J., Mayer, M. L. & Lau, A. Y. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure 21, 1788–99 (2013).

      11.        Johnson, J. W. & Ascher, P. Voltage-dependent block by intracellular Mg2+ of N-methyl-D-aspartate-activated channels. Biophys. J. 57, 1085–90 (1990).

      12.        Purves, D., Augustine, G. J. & Fitzpatrick, D. Neuroscience, 4th Edition. Nature Reviews Neuroscience (2008). doi:978-0878937257

      13.        Zhou, Q. & Sheng, M. NMDA receptors in nervous system diseases. Neuropharmacology 74, 69–75 (2013).

      14.        Lerma, J. Roles and rules of kainate receptors in synaptic transmission. Nat. Rev. Neurosci. 4, 481–495 (2003).

      15.        Bowie, D. Ion-dependent gating of kainate receptors. J. Physiol. 588, 67–81 (2010).

      16.        Plested, A. J. R. Kainate receptor modulation by sodium and chloride. Adv. Exp. Med. Biol. 717, 93–113 (2011).

      17.        Lerma, J. & Marques, J. M. Kainate receptors in health and disease. Neuron 80, 292–311 (2013).