title: G protein-coupled receptor kinase-mediated desensitization of metabotropic glutamate receptor 1A protects against cell death.
abstract: Metabotropic glutamate receptors (mGluRs) constitute a unique subclass of G protein-coupled receptors (GPCRs) that bear little sequence homology to other members of the GPCR superfamily. The mGluR subtypes that are coupled to the hydrolysis of phosphoinositide contribute to both synaptic plasticity and glutamate-mediated excitotoxicity in neurons. In the present study, the expression of mGluR1a in HEK 293 cells led to agonist-independent cell death. 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 overactivation. We find that the co-expression of mGluR1a with GRK2 and GRK5, but not GRK4 and GRK6, reduced both constitutive and agonist-stimulated mGluR1a activity. Agonist-stimulated mGluR1a phosphorylation was enhanced by the co-expression of GRK2 and was blocked by two different GRK2 dominant-negative mutants. Furthermore, GRK2-dependent mGluR1a desensitization protected against mGluR1a-mediated cell death, at least in part by blocking mGluR1a-stimulated apoptosis. Our data indicate that as with other members of the GPCR superfamily, a member of the structurally distinct mGluR family (mGluR1a) serves as a substrate for GRK-mediated phosphorylation and that GRK-dependent "feedback" modulation of mGluR1a responsiveness protects against pathophysiological mGluR1a signaling.
authors.affiliation: John P. Robarts Research Institute, London, Ontario N6A 5K8, Canada.
authors.forename: L B
authors.initials: LB
authors.lastname: Dale
authors.forename: M
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: P H
authors.initials: PH
authors.lastname: Anborgh
authors.forename: B
authors.initials: B
authors.lastname: Murdoch
authors.forename: M
authors.initials: M
authors.lastname: Bhatia
authors.forename: S
authors.initials: S
authors.lastname: Nakanishi
authors.forename: S S
authors.initials: SS
authors.lastname: Ferguson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D054771:G-Protein-Coupled Receptor Kinase 4; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D007295:Inositol Phosphates; D010446:Peptide Fragments; D010710:Phosphates; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C104077:metabotropic glutamate receptor type 1; D016318:Quisqualic Acid; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517855:GRK4 protein, human; C517898:GRK5 protein, human; C517854:Grk4 protein, rat; C517897:Grk5 protein, rat; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium