Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems

The metabotropic glutamate receptor, mGluR5, has a critical role in inducti on of NMDA-receptor-dependent forms of synaptic plasticity and excitotoxici ty. This is likely mediated by a reciprocal positive-feedback interaction b etween these two glutamate receptor subtypes in which activation of mGluR5 potentiates NMDA receptor currents and NMDA receptor activation potentiates mGluR5-mediated responses. We have investigated the mechanism by which NMD A receptor activation modulates mGluR5 function and find evidence that this response is mediated by activation of a protein phosphatase and a resultan t dephosphorylation of protein kinase C phosphorylation sites on mGluR5. Th is form of neuromodulation may be important in a number of normal and patho logical processes that involve activation of the NMDA receptor.