Phosphorylation and Chronic Agonist Treatment Atypically Modulate GABAB Receptor Cell Surface Stability
| Autor: | Andrew R. Calver, Benjamin P. Fairfax, Andrés Couve, Stephen J. Moss, Mark G.H. Scott, Julie A. Pitcher, Menelas N. Pangalos |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Baclofen
Time Factors Hippocampus Biochemistry Cyclic AMP Phosphorylation Receptor Cells Cultured Cerebral Cortex Neurons Arrestin Temperature Endocytosis Cell biology COS Cells Signal transduction Dimerization Plasmids Protein Binding Agonist medicine.medical_specialty DNA Complementary medicine.drug_class GABAB receptor Biology Cell Line Internal medicine Receptors Adrenergic beta medicine Animals Humans Biotinylation GABA Agonists Molecular Biology GABA-B Receptor Agonists Cell Membrane Cell Biology Cyclic AMP-Dependent Protein Kinases Precipitin Tests Rats Enzyme Activation Metabotropic receptor Endocrinology Microscopy Fluorescence Receptors GABA-B nervous system Calcium |
| Zdroj: | JOURNAL OF BIOLOGICAL CHEMISTRY Artículos CONICYT CONICYT Chile instacron:CONICYT |
| ISSN: | 0021-9258 |
| Popis: | GABA(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. The dynamic control of the cell surface stability of GABA(B) receptors is likely to be of fundamental importance in the modulation of receptor signaling. Presently, however, this process is poorly understood. Here we demonstrate that GABA(B) receptors are remarkably stable at the plasma membrane showing little basal endocytosis in cultured cortical and hippocampal neurons. In addition, we show that exposure to baclofen, a well characterized GABA(B) receptor agonist, fails to enhance GABA(B) receptor endocytosis. Lack of receptor internalization in neurons correlates with an absence of agonist-induced phosphorylation and lack of arrestin recruitment in heterologous systems. We also demonstrate that chronic exposure to baclofen selectively promotes endocytosis-independent GABA(B) receptor degradation. The effect of baclofen can be attenuated by activation of cAMP-dependent protein kinase or co-stimulation of beta-adrenergic receptors. Furthermore, we show that increased degradation rates are correlated with reduced receptor phosphorylation at serine 892 in GABA(B)R2. Our results support a model in which GABA(B)R2 phosphorylation specifically stabilizes surface GABA(B) receptors in neurons. We propose that signaling pathways that regulate cAMP levels in neurons may have profound effects on the tonic synaptic inhibition by modulating the availability of GABA(B) receptors. |
| Databáze: | OpenAIRE |
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