Cyclic AMP-dependent protein kinase phosphorylation facilitates GABA(B) receptor-effector coupling.
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.
Couve
A
A
Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Thomas
P
P
Calver
A R
AR
Hirst
W D
WD
Pangalos
M N
MN
Walsh
F S
FS
Smart
T G
TG
Moss
S J
SJ
D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D016466:CHO Cells; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism; D020033:Protein Isoforms / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D051381:Rats; D018080:Receptors, GABA-B / Q000032:analysis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D010750:Phosphoproteins; D015221:Potassium Channels; D020033:Protein Isoforms; D018080:Receptors, GABA-B; D011994:Recombinant Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases