Metabotropic glutamate receptors: from the workbench to the bedside

Abstract

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson's disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Fig. 1

Modular structure of mGlu receptors. a) Ribbon view of the open (left) and closed (right) mGlu1 receptor Venus Fly Trap (VFT) bound with glutamate (back). Images were prepared using the coordinates of the glutamate-bound mGlu1 receptor VFT dimer (pdb 1EWK), in which one VFT is closed while the other is open. b) Side view of the mGlu1 receptor dimer bearing the VFT in its empty “resting” state (left) (pdb 1EWT), or agonist occupied “active” orientation (right) (pdb 1EWK). The front VFT is in light grey, while the one in the back is black. c) General organization of an mGlu receptor deduced from the structure of the dimeric mGlu3 extracellular domain (VFT + CRD) (pdb 1E4U) associated with two rhodopsinlike 7-TM domains.

Fig. 2

Protein–protein interactions involving group-I mGlu receptors in the post-synaptic densities. Long isoforms of Homer proteins allows the formation of multi-molecular complexes including mGlu1 and mGlu5 receptors. Interactions with NMDA receptors, TrpC ion channels, inositol-1,4,5-trisphosphate receptors (InsP3R), or PIKE-L are shown. Short Homer1a lacking the coiled-coil domain disrupts the formation of the multimolecular complex, thereby affecting mGlu1/5 receptor signalling.

Fig. 3

Synaptic distribution of group-II and group-III mGlu receptors. Note that presynaptic mGlu2/3 receptors are located in the pre-terminal regions of the axons, where they can be activated by glutamate released from astrocytes via the cystine/ glutamate antiporter. In contrast, presynaptic mGlu4/7/8 receptors are located near to the active zone of neurotransmitter release. Glial mGlu3 receptors induce the formation and secretion of TGF-β. The presence of mGlu5 receptors in glial cells is also shown.

Fig. 4

Localization and function of mGlu6 receptors in retinal ON-bipolar cells. mGlu6 receptors are present in the dendrites of the ON-bipolar cells of the retina, where their activation negatively modulates TrpM1 channels through a chain of events that include intracellular calcium release and activation of the protein phosphatase, calcineurin.