526 Activation of N-Methyl-D-Aspartate Receptors Reverses Desensitization of Metabotropic Glutamate Receptor, mGluR5, in Native and Recombinant Systems S. ALAGARSAMY, a S. T. ROUSE, a R. W. GEREAU IV, b S. F. HEINEMANN, b Y. SMITH, c AND P. J. CONN a,d a Department of Pharmacology, Division of Neuroscience, Emory University School of Medicine, Atlanta, Georgia 30322, USA b Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA c Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA lutamate, the primary excitatory neurotransmitter in the central nervous system, elic- its fast excitatory synaptic responses by activation of glutamate-gated cation channels termed ionotropic glutamate receptors (iGluRs). 1 Glutamate also modulates synaptic trans- mission and cell excitability by activation of G protein–coupled receptors, termed metabo- tropic glutamate receptors (mGluRs). 2 The NMDA receptor is unique among the ionotropic glutamate receptors in its critical role in formation of new memory and other forms of synaptic plasticity. 1 In addition, excessive activation of NMDA receptors leads to excitotoxicity that may participate in cell death associated with a variety of pathological conditions, including stroke, seizure activ- ity, and certain neurodegenerative disorders. 1 Interestingly, one of the most prominent effects of mGluR activation in a number brain regions is an enhancement of agonist- evoked currents through the NMDA receptor cation channel. 3 In hippocampus and other cortical regions, this response is likely mediated by mGluR5. 3 Recent studies in hippocam- pal and cortical slices suggest that activation of NMDA receptors can also potentiate responses to activation of mGluR5. 4,5 This positive feedback reciprocal regulation between mGluR5 and NMDA receptors may play an important role in regulating NMDA receptor- dependent forms of synaptic plasticity and could contribute to pathological responses to NMDA receptor activation. However, little is known about the mechanisms by which NMDA receptor activation potentiates mGluR5-mediated responses. Recent studies suggest that mGluR5 undergoes a rapid agonist-induced desensitization that is mediated by activation of protein kinase C (PKC) and PKC-mediated phosphoryla- tion of identified serine residues on mGluR5. 6 This, coupled with previous findings that NMDA receptor activation can lead to activation of calcium-dependent serine/threonine phosphatases, 7 led us to postulate that mGluR5 and NMDA receptor subunits are colocal- d Address for correspondence: P. Jeffrey Conn, Rollins Research Building, Department of Phar- macology, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322. Phone: 404-727-5617; fax: 404-727-0365; e-mail: jconn@pharm.emory.edu G