Roles of group I metabotropic glutamate receptors under physiological conditions and in neurodegeneration

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 For further resources related to this article, please visit the WIREs website. Conflict of interest: MB and JMB have a conflict of interest. The University of Southern California holds an equity interest in Rhenovia Pharma, and has also received licensing income from Rhenovia Pharma.