Phosphorylation-independent desensitization of GABAB receptor by GRK4
AUTOR(ES)
Perroy, Julie
FONTE
Oxford University Press
RESUMO
Agonist-promoted desensitization of the heterodimeric metabotropic GABAB receptor was investigated. Whereas no desensitization was observed in HEK293 cells heterologously expressing the receptor, GABA and the synthetic agonist baclofen induced a robust desensitization in cerebellar granule cells endogenously expressing the receptor. Taking advantage of this cell-specific desensitization phenotype, we identified GRK4 as the kinase involved in the neuronal desensitization. Transfection of small interference RNA directed against GRK4 significantly reduced GRK4 levels in cerebellar granule cells and strongly inhibited the agonist-promoted desensitization. Reciprocally, transfection of GRK4 in HEK293 cells restored agonist-promoted desensitization, confirming that this kinase is sufficient to support desensitization. Surprisingly, this desensitization occurred in the absence of ligand-induced receptor phosphorylation and could be promoted by GRK4 mutants deleted of their kinase domain. Taken together, these results suggest that GRK4 plays a central role in the agonist-promoted desensitization of GABAB receptor and that it does so through an atypical mechanism that challenges the generally accepted model linking the kinase activity of GRKs to their role in receptor desensitization.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=169056Documentos Relacionados
- Phosphorylation-independent Regulation of Metabotropic Glutamate Receptor 5 Desensitization and Internalization by G Protein-coupled Receptor Kinase 2 in Neurons*
- Phosphorylation-independent inhibition of parathyroid hormone receptor signaling by G protein-coupled receptor kinases
- Diacylglycerol analogs inhibit the rod cGMP-gated channel by a phosphorylation-independent mechanism.
- Phosphorylation-independent bacterial chemoresponses correlate with changes in the cytoplasmic level of fumarate.
- Phosphorylation-Independent Inhibition of Cdc28p by the Tyrosine Kinase Swe1p in the Morphogenesis Checkpoint