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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.

Original publication

DOI

10.1074/jbc.m311389200

Type

Journal

The Journal of biological chemistry

Publication Date

03/2004

Volume

279

Pages

12565 - 12573

Addresses

Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.

Keywords

Hippocampus, Cerebral Cortex, Neurons, Cells, Cultured, Cell Line, COS Cells, Cell Membrane, Animals, Humans, Rats, Calcium, Baclofen, Cyclic AMP-Dependent Protein Kinases, Arrestin, Receptors, Adrenergic, beta, Receptors, GABA-B, DNA, Complementary, Cyclic AMP, GABA Agonists, Microscopy, Fluorescence, Precipitin Tests, Biotinylation, Temperature, Endocytosis, Enzyme Activation, Protein Binding, Dimerization, Phosphorylation, Plasmids, Time Factors, GABA-B Receptor Agonists