ROLE OF PROTEIN-KINASE-C PHOSPHORYLATION IN RAPID DESENSITIZATION OF METABOTROPIC GLUTAMATE-RECEPTOR-5

Metabotropic glutamate receptors (mGluRs) coupled to phosphoinositide hydrolysis desensitize in response to prolonged or repeated agonist ex posure, and evidence suggests that this involves activation of protein kinase C (PKC). The present studies were undertaken to determine if c loned mGluR5 undergoes similar PKC-mediated desensitization and to inv estigate the molecular mechanism underlying PKC-induced desensitizatio n. In Xenopus oocytes, both mGluR5a and mGluR5b showed pronounced dese nsitization in response to a brief activation by glutamate. Pharmacolo gical studies clearly suggest that this desensitization requires PKC-m ediated phosphorylation. Analysis of PKC consensus phosphorylation sit e mutants suggests that PKC phosphorylates mGluR5 at multiple sites to induce a relatively rapid form of desensitization. Because mGluRs pla y important roles in synaptic plasticity and in excitotoxicity, this d esensitization may be involved in the dynamic regulation of these proc esses.