Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert

Abstract

Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range of spatial and temporal scales. This functional diversity is decoded by two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The challenges posed by the complexity and physiological importance of each of these subtypes has limited our appreciation and understanding of how these receptors work in concert. In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.

Keywords: G protein-coupled receptor; glutamate receptor; iGluR; ion channel; mGluR; neuromodulation; neurotransmitter; optogenetics; receptor crosstalk; synapse; synaptic plasticity.

Figure 1.. iGluRs and mGluRs: Structural Organization, Glutamate Sensitivity, and Kinetics

(A) Top: domain organization of iGluRs (green) and mGluRs (blue). Glutamate and orthosteric ligands bind in the inter-lobe cleft of the ligand binding domains (LBDs). In both receptor classes, various ions bind near the orthosteric site, in the inter-LBD dimer interface, and the amino terminal domain (ATD) of iGluRs. Positive or negative allosteric modulators of mGluRs bind in the transmembrane domain (TMD), whereas allosteric modulators of iGluRs bind in the ATD or LBD, and pore blockers bind within the ion channel-forming TMD. Bottom: phylogenetic trees showing the iGluR and mGluR subfamilies and their subunits. (B) Top: diagram summarizing synaptically relevant glutamate concentrations. Bottom: glutamate sensitivities (centered around EC₅₀) of mGluRs and iGluRs cover a broad range and show a major overlap. (C) Timescales of synaptic transmission and plasticity (top) and the associated timing of GluR gating and downstream signaling (bottom). The fastest iGluRs, AMPARs and KARs, mediate millisecond responses and enable high-frequency synaptic transmission. Both mGluRs and iGluRs allow sensing and signal transduction (timescale of tens of milliseconds) to control many forms of short-term (seconds to minutes) and long-term synaptic plasticity (hours). Precisely defining these timescales remains an important challenge, particularly for mGluRs in the synaptic context where few high-resolution, direct measurements have been made.

Figure 2.. Potential Mechanisms of Crosstalk between iGluRs and mGluRs

(A) iGluRs and mGluRs may interact directly to modulate each other, as exemplified by potential direct interaction between the CTDs of group I mGluRs and NMDARs.. (B) Synaptic scaffolding proteins that interact with both GluR classes provide ample opportunities for crosstalk in the form of bridging between different receptor complexes (e.g., for group I mGluRs and NMDARs via Homer-SHANK-DLGAP-PSD-95) or competition for the same scaffold (e.g., PICK1, which contains a common binding site for mGluR7 and AMPARs).. (C) Downstream signals that are activated by iGluRs and mGluRs via overlapping or distinct mechanisms allow crosstalk, as illustrated by the shared second messenger Ca²⁺ (orange circles). Glutamate-evoked channel opening of iGluRs produces Ca²⁺ influx, whereas group I mGluRs induce Ca²⁺ release from intracellular stores. Both iGluRs and mGluRs can modulate the function of voltage-gated Ca²⁺ channels (VGCCs), and elevations in cytosolic Ca²⁺ can lead to Ca²⁺-induced Ca²⁺ release (CICR) from the ER, providing many opportunities for crosstalk where Ca²⁺ signals act cooperatively to control cellular processes.. (D) Transcription and translation are controlled by iGluR and mGluR signaling. Regulating the expression of receptor subtypes, key scaffolds, regulators, or effectors provides a powerful form of positive or negative synergism. (E) By initiating a number of second messenger and phosphorylation-mediated signaling cascades, mGluRs and iGluRs serve as mutual effectors of each other. Left: summary of major paths of inter-class receptor regulation. Solid lines indicate potentiation or inhibition that has been clearly demonstrated, whereas dotted red lines indicate that insufficient analysis has been performed for this combination. Right: one example of reciprocal regulation is group I mGluR-mediated control of AMPAR internalization, which occurs via a kinase cascade that has not been fully elucidated.

Figure 3.. Concerted GluR Signaling at the Synapse

(A) Left: iGluRs and mGluRs show overlapping expression patterns in all major neuronal cell types as well as astrocytes. The exact expression levels and receptor subtypes are not known and may vary between cells but also between individual synapses. Expression of iGluRs in glia is particularly ill-defined and appears to be regional. Glial NMDARs, which might include GluN2C/D and GluN3 subunits most prominently, remain contro-versial. Right: iGluRs and mGluRs are present in all synaptic compartments; i.e., the presynaptic terminal, the postsynaptic density, perisynaptic regions, and astrocytic processes. The precise ultrastructural localization determines the timing and concentration of glutamate-induced activation and defines both downstream signaling and the potential for functional crosstalk. (B) GluR crosstalk in the induction of postsynaptic plasticity. This schematic focuses on the distinct pathways employed by NMDARs and mGluR5 in the induction of LTD in hippocampal neurons. Both pathways converge on the internalization of AMPARs but may target distinct populations. (C) GluR contribution to presynaptic forms of plasticity, as illustrated by the dual roles of group II mGluRs and KARs in presynaptic LTD and LTP at hippocampal mossy fiber synapses and their convergence on regulation of release probability. The factors that determine whether KARs are excitatory or inhibitory and the signaling pathway downstream of PKA remain unclear.