Since their cloning in 1991, metabotropic glutamate receptors (mGluRs) have been the subject of numerous studies, as it rapidly
became apparent that this class of G‐protein coupled receptors (GPCRs) participated in numerous functions in the central nervous
system. Group I mGluR receptors function chiefly postsynaptically, as modulators of the ionotropic AMPA and NMDA glutamate
receptors, and triggers of intracellular signaling pathways that could lead to long‐term modifications of synaptic efficacy
and to neurodegeneration. It is now clear that the activation of group I mGluR receptors has only minimum effects on synaptic
transmission and regulation at low level of presynaptic activity; in contrast, they become engaged and exert potent effects
on intracellular cascades at high frequency of stimulation. Moreover, when postsynaptic calcium reaches levels sufficient
to activate the calcium‐dependent protease calpain, calpain truncates the C‐terminal domain of mGluR1α and changes its signaling properties to make it exclusively neurodegenerative. A new method using the transmembrane transport
properties of the tat‐peptide prevents neuronal degeneration following excessive activation of the NMDA receptors, which could
occur in ischemia and various forms of excitotoxicity. Caution should be observed, however, regarding the numerous phenomena
observed following the prolonged activation of group I mGluRs by exogenous agonists. WIREs Membr Transp Signal 2012, 1:523–532. doi: 10.1002/wmts.51
Glutamate transients following single synaptic release in a CA3‐CA1 synapse. (a) Simulated glutamate concentration after single synaptic vesicle release (3000 glutamate molecules) at various distances from release site. The influence of glutamate transporters can be seen by comparing curves generated with (green) and without (blue) specific glutamate uptake. Note the order‐of‐magnitude changes in glutamate concentration scale and progressive change in time scale with increasing distance from release site. (b) Peak extracellular glutamate concentration and area under the curve (AUC) versus location for the simulated transients in (a). (c) Schematic representation of a glutamate‐releasing synapse and a neighboring synapse on dendritic spines of CA1, showing extrasynaptic group I mGluRs and the distances (dashed arcs) at 20, 100, 500, and 1000 nm after single release with glutamate transporters. The concentration peaks were derived from the simulations in (a).
Schematic representation of the signaling pathways for group I mGluRs at a glutamatergic synapse. Following glutamate release from the presynaptic element, and glutamate diffusion in the synaptic cleft, glutamate binds and activates the ionotropic receptors, AMPA and NMDA, as well as group I metabotropic glutamate receptors, i.e., mGluR1 and mGluR5. These receptors are generally assumed to be located at the periphery of the postsynaptic density and even in the perisynaptic region. Once activated these receptors activate a Gq protein, resulting in the activation of PLCβ, and the production of IP3 and DAG. IP3 in turn activates an IP3 receptor, located in the membrane of the endoplasmic reticulum inducing the release of calcium. Another source of calcium is provided by the activation of NMDA receptors and the resulting calcium influx through the NMDA receptor‐channel. When intracellular calcium reaches a concentration high enough to activate the calcium‐dependent protease calpain, this enzyme truncates the C‐terminal domain of mGluR1, eliminating the links between the receptor and the PI3K/Akt neuroprotective signaling pathway, but leaving intact the link between the receptor and the release of calcium from endoplasmic reticulum. This produces an exclusively neurodegenerative form of mGluR1, which is responsible for neuronal damage following ischemia and excitotoxic conditions, such as in epilepsy.
Submit a note to the editor about this article by filling in the form below.
* Required Field
Thank you for submitting your Editor note. Your information was successfully submitted.
How to Cite
Baudry Michel, Greget Renaud, Pernot Fabien, Bouteiller Jean‐Marie, Xiaoning Bi. Roles of group I metabotropic glutamate receptors under physiological conditions and in neurodegeneration. WIREs Membr Transp Signal 2012, 1: 523-532. doi: 10.1002/wmts.51
Access to this WIREs title is FREE for members of registered institutions.