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

被引:96
作者
Couve, A
Thomas, P
Calver, AR
Hirst, WD
Pangalos, MN
Walsh, FS
Smart, TG
Moss, SJ
机构
[1] UCL, MRC, Mol Cell Biol Lab, London WC1E 6BT, England
[2] UCL, Dept Pharmacol, London WC1E 6BT, England
[3] Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England
[4] GlaxoSmithKline Inc, Neurol Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
关键词
D O I
10.1038/nn833
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:415 / 424
页数:10
相关论文
共 33 条
[1]  
Brandon NJ, 1999, J NEUROSCI, V19, P9228
[2]   G-protein coupled receptor kinases as modulators of G-protein signalling [J].
Bünemann, M ;
Hosey, MM .
JOURNAL OF PHYSIOLOGY-LONDON, 1999, 517 (01) :5-23
[3]   Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors [J].
Cai, ZH ;
Saugstad, JA ;
Sorensen, SD ;
Ciombor, KJ ;
Zhang, CX ;
Schaffhauser, H ;
Hubalek, F ;
Pohl, J ;
Duvoisin, RM ;
Conn, PJ .
JOURNAL OF NEUROCHEMISTRY, 2001, 78 (04) :756-766
[4]   The expression of GABAB1 and GABAB2 receptor subunits in the CNS differs from that in peripheral tissues [J].
Calver, AR ;
Medhurst, AD ;
Robbins, MJ ;
Charles, KJ ;
Evans, ML ;
Harrison, DC ;
Stammers, M ;
Hughes, SA ;
Hervieu, G ;
Couve, A ;
Moss, SJ ;
Middlemiss, DN ;
Pangalos, MN .
NEUROSCIENCE, 2000, 100 (01) :155-170
[5]  
Calver AR, 2001, J NEUROSCI, V21, P1203
[6]   Binding of the inward rectifier K+ channel Kir 2.3 to PSD-95 is regulated by protein kinase A phosphorylation [J].
Cohen, NA ;
Brenman, JE ;
Snyder, SH ;
Bredt, DS .
NEURON, 1996, 17 (04) :759-767
[7]   GABAB receptor:: A new paradigm in G protein signaling [J].
Couve, A ;
Moss, SJ ;
Pangalos, MN .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2000, 16 (04) :296-312
[8]   Intracellular retention of recombinant GABAB receptors [J].
Couve, A ;
Filippov, AK ;
Connolly, CN ;
Bettler, B ;
Brown, DA ;
Moss, SJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (41) :26361-26367
[9]   Association of GABAB receptors and members of the 14-3-3 family of signaling proteins [J].
Couve, A ;
Kittler, JT ;
Uren, JM ;
Calver, AR ;
Pangalos, MN ;
Walsh, FS ;
Moss, SJ .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2001, 17 (02) :317-328
[10]  
HIRST WD, 2000, BRIT J PHARMACOL, V129, P80