G protein coupled receptor kinase-mediated desensitization of metabotropicglutamate receptor 1A protects against cell death

Metabotropic glutamate receptors (mGluRs) constitute a unique subclass of G protein-coupled receptors (GPCRs) that bear little sequence homology to ot her members of the G;PCR superfamily. The mGluR subtypes that are coupled t o the hydrolysis of phosphoinositide contribute to both synaptic plasticity and glutamate-mediated excitotoxicity in neurons. In the present study, th e expression of mGluR1a in HEK 293 cells led to agonist-independent cell de ath. Since G protein-coupled receptor kinases (GRKs) desensitize a diverse variety of GPCRs, we explored whether GRKs contributed to the regulation of both constitutive and agonist-stimulated mGluR1a activity and thereby may prevent mGluR1a-mediated excitotoxicity associated with mGluR1a overactivat ion. We find that the co-expression of mGluR1a with GRK2 and GRK5, but not GRK4 and GRK6, reduced both constitutive and agonist-stimulated mGluR1a act ivity. Agonist-stimulated mGluR1a phosphorylation was enhanced by the co-ex pression of GRK2 and was blocked by two different GRK2 dominant-negative mu tants. Furthermore, GRK2-dependent mGluR1a desensitization protected agains t mGluR1a-mediated cell death, at least in part by blocking mGluR1a-stimula ted apoptosis. Our data indicate that as with other members of the GPCR sup erfamily, a member of the structurally distinct mGluR family (mGluR1a) serv es as a substrate for GRK-mediated phosphorylation and that GRK-dependent " feedback" modulation of mGluR1a responsiveness protects against pathophysio logical mGluR1a signaling.