G Protein-coupled Receptor Kinase-mediated Desensitization of Metabotropic Glutamate Receptor 1A Protects against Cell Death

Sep 13, 2000The Journal of biological chemistry

How a protein kinase reduces sensitivity of a brain receptor to protect cells from dying

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Abstract

Co-expression of mGluR1a with GRK2 and GRK5 reduced both constitutive and agonist-stimulated mGluR1a activity.

mGluR1a expression in HEK 293 cells caused agonist-independent cell death.
GRK2 and GRK5, but not GRK4 and GRK6, were found to modulate mGluR1a activity.
Co-expression of GRK2 enhanced mGluR1a phosphorylation during agonist stimulation.
Dominant-negative mutants of GRK2 blocked this phosphorylation enhancement.
GRK2-mediated desensitization of mGluR1a provided protection against cell death linked to mGluR1a overactivation.

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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.

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G Protein-coupled Receptor Kinase-mediated Desensitization of Metabotropic Glutamate Receptor 1A Protects against Cell Death

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