Glutamatergic Receptors Dynamics and Regulation

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Background

Glutamate is the major excitatory transmitter in the CNS, and activation of its receptors underlies most excitatory synaptic transmission in the brain. Depending on how glutamate binds to its receptor and how the posterior signaling cascade occurs, these can be defined as ionotropic receptors, named after their selective agonists, and which comprise 𝜶-amino-3-hydroxy-5-mehyl-4-isoxazolepropionic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and Kainate receptors (KARs); and as G protein-coupled metabotropic receptors. They all form dimers-of-dimers, and each monomer comprises an extracellular amino-terminal domain, a more or less complex transmembrane domain with a ligand binding domain, and a cytoplasmic carboxyl terminal domain, which, in some cases, is subject to subunit-specific regulation.

Ionotropic receptors share a general heterotetrameric structure. GluA1-GluA4 form AMPARs; GluN1, GluN2A-GluN2D, GluN3A to 3B are involved in the formation of the NMDARs; and KARs are assembled by the combination of GluK1-3 with GluK4 or GluK5.

The speed and duration of AMPAR-mediated synaptic currents varies significantly depending on AMPAR subunit composition and on the splice variant (flip or flop) involved. Also, depending on whether they are GluA2 lacking or containing receptors, and to which extent its mRNA is edited, their Ca2+ permeability can be affected.

NMDAR-mediated synaptic currents show much slower kinetics and much higher permeability to Ca2+, than AMPARs, although these properties are also dependent on their subunit composition. They are blocked by Mg2+ at resting membrane potential. As a consequence, they only allow ions influx when the membrane depolarizes, thus relieving the Mg2+ block and when their ligand is present.

KARs are both pre- and post-synaptic, and they have smaller currents and slower deactivation kinetics than AMPARs. Far less characterized, they have been shown to play a role in regulating both excitatory and inhibitory transmission.

Metabotropic receptors can also be classified in 3 different groups: I (mGluR1,5), II (mGluR2,3) and III (mGluR4,6,7,8) depending on their localization and mechanism of action. Group I receptors are mainly post-synaptic and act by coupling to the G protein Gq, activating the phospholipase C-phosphoinositide pathway (PLC-PI). Group II receptors are also post-synaptically represented, but they have a strong presence in the pre-synaptic compartment, where they are coupled to G protein G0, inhibiting Ca2+ channels and, therefore, inhibiting neurotransmitter release in a negative feedback manner. Lastly, Group III receptors are also predominantly pre-synaptic (except in the ON-bipolar retinal cells), and they also work by inhibiting adenylyl cyclase and Ca2+ channels, and activating K+ ones.

It is clear that to achieve specificity within such a plethora of receptors for the same ligand, every step of the pathway, from the synthesis to the membrane insertion and activation, has to be tightly regulated. The contributors to this Research Topic can offer significant insight into every one of those different steps. It’s been more than 50 years since glutamate was first proposed to be a neurotransmitter, and yet the field is still growing with excitement. The collection of papers presented here will certainly contribute to both maintain the excitement and broaden our knowledge.

Keywords: glutamate, synaptic transmission, glutamate-receptors, plasticity

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