Metabotropic glutamate receptors: intracellular signaling pathways

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Metabotropic glutamate receptors are classified into three groups, primarily on the basis of sequence similarity and whether they positively couple to the phospholipase C cascade or negatively couple to adenylyl cyclases. The past decade of research, drawing on sophisticated molecular approaches, has revealed a multitude of additional intracellular components that assemble as protein scaffolds around neuronal metabotropic glutamate receptors, establishing functional links to postsynaptic density structures, to membrane-bound enzymes and ion channels, and to the nucleus. Characterization of these novel transduction mechanisms is providing new insights into the roles of metabotropic glutamate receptors in the regulation and modulation of diverse functions in the nervous system.

Introduction

The metabotropic glutamate receptors (mGluRs) were discovered when it was observed that exposing neurons to glutamate activated not only ionotropic receptors but also stimulated phospholipase C (PLC) [1, 2]. Soon thereafter, a family of eight distinct mGluR subtypes was identified, and the palette of associated intracellular signaling mechanisms was greatly extended [3]. The mGluRs are classified according to structural and functional criteria into Group I (mGluR1 and mGluR5), Group II (mGluR2 and mGluR3), and Group III (mGluR4, mGluR6, mGluR7, and mGluR8) [4]. Here, we provide a brief update of new developments that expand and clarify our understanding of the transduction mechanisms mediating responses initiated by mGluRs. A major advance in this field, the retrograde signaling by endocannabinoids following the activation of postsynaptic mGluRs, will not be discussed explicitly here as this topic is the subject of several comprehensive recent reviews (e.g. see [5]).

Section snippets

Transduction within the mGluR

Upon binding of glutamate, a conformational change in homodimeric mGluRs promotes the coupling of G proteins to specific intracellular domains. Structural studies, beginning with the crystallization and characterization of the agonist-bound and ‘unliganded’ forms of the glutamate binding site of mGluR1, provided initial insights into the underlying process [6]. Agonist binding stabilizes the closed conformation of the extracellular domain and results in G protein activation that is dependent

G-protein-independent signaling

The canonical cascade coupling metabotropic receptors with their intracellular effectors begins with the activation of G proteins, hence the name G-protein-coupled receptors. Over the past decade, however, several studies have reported metabotropic responses that do not involve G proteins [11]. Evidence that mGluRs can also function in this manner came from experiments showing that activation of mGluR1 in hippocampal neurons simultaneously triggers both G-protein-dependent and -independent

β-arrestins and mGluR signaling

Following their activation, metabotropic receptors undergo rapid desensitization through a process involving phosphorylation by G-protein-coupled receptor kinases, which then allows the binding of the adaptor proteins β-arrestin 1 and β-arrestin 2 that direct receptor endocytosis through targeting to clathrin-coated pits [17]. This mechanism also holds for the mGluRs, although a phosphorylation-independent form of desensitization mediated by G-protein-coupled receptor kinase-2 has been

Ubiquitous actions of calcium

Almost every step in the signaling pathways associated with mGluRs requires, or is modulated by, calcium. Beginning with the receptors themselves, both the potency and efficacy of glutamate action at Group I mGluRs is enhanced with increasing concentrations of extracellular calcium [20]. Importantly, the efficacy of mGluR signaling is modulated by physiologically relevant changes in extracellular calcium, such that calcium depletion in the synaptic cleft, as occurs during burst firing, causes

Modulation of transcription and translation by mGluRs

The consolidation of synaptic plasticity is dependent upon protein synthesis. The ability of mGluRs to initiate this process was shown by studies demonstrating a role for mGluR-dependent protein synthesis in the maintenance of epileptiform discharge [31] and in hippocampal synaptic plasticity [32, 33]. Interestingly, the protein synthesis necessary for mGluR-dependent hippocampal LTD depends upon local translation of mRNA near the synapse, and not upon transcription [32]. Concurrently, it was

Conclusions and outlook

mGluRs play key roles in the modulation of diverse cellular responses. Recent structural advances have provided new insights into how changes in receptor conformation can initiate response transduction. In addition, molecular analysis is providing rich detail into the surprisingly divergent signaling pathways employed by these receptors, which modulate targets not only in the membrane but also in the cytoplasm and nucleus.

Although metabotropic receptors and the responses they mediate are

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the laboratory of Urs Gerber is supported by the Swiss National Science Foundation and the NCCR on Neural Plasticity and Repair.

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