Cyclic AMP–dependent protein kinase phosphorylation facilitates GABAB receptor–effector coupling

• DOI: 10.1038/nn833
• Publication Date: 2002-07-26T08:31:14Z
• Authors: Andrés Couve; Philip Thomas; Andrew R. Calver; Warren D. Hirst; Menelas N. Pangalos; Frank S. Walsh; Trevor G. Smart; Stephen J. Moss
• Keywords: Brain Chemistry; Neurons; 0303 health sciences; Patch-Clamp Techniques; Potassium Channels; Cell Membrane; Brain; CHO Cells; Phosphoproteins; Cyclic AMP-Dependent Protein Kinases; 03 medical and health sciences; Cricetinae; GABA-B Receptor Agonists; COS Cells; Cyclic AMP; Animals; Humans; Protein Isoforms; Enzyme Inhibitors; Phosphorylation; GABA Agonists; Cells, Cultured

GABA (gamma-aminobutyric acid)(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA). Basal phosphorylation of this residue is evident in rat brain membranes and in cultured neurons. Phosphorylation of Ser892 is modulated positively by pathways that elevate cAMP concentration, such as those involving forskolin and beta-adrenergic receptors. GABA(B) receptor agonists reduce receptor phosphorylation, which is consistent with PKA functioning in the control of GABA(B)-activated currents. Mechanistically, phosphorylation of Ser892 specifically enhances the membrane stability of GABA(B) receptors. We conclude that signaling pathways that activate PKA may have profound effects on GABA(B) receptor-mediated synaptic inhibition. These results also challenge the accepted view that phosphorylation is a universal negative modulator of G protein-coupled receptors.