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

Nature Neuroscience volume 5, pages 415424 (2002) | Download Citation

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Abstract

GABA (γ-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 GABABR1/GABABR2 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 GABABR2 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 β-adrenergic receptors. GABAB receptor agonists reduce receptor phosphorylation, which is consistent with PKA functioning in the control of GABAB-activated currents. Mechanistically, phosphorylation of Ser892 specifically enhances the membrane stability of GABAB receptors. We conclude that signaling pathways that activate PKA may have profound effects on GABAB receptor–mediated synaptic inhibition. These results also challenge the accepted view that phosphorylation is a universal negative modulator of G protein–coupled receptors.

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Acknowledgements

We thank C. Sinjin, F. Bedford, J. Kittler and V. Tretter for supplying cultures of cortical and hippocampal neurons, and J. Pitcher for critically reading the manuscript. A.C. was supported by The Wellcome Trust.

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Affiliations

  1. Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK

    • Andrés Couve
    •  & Stephen J. Moss
  2. Department of Pharmacology, School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK

    • Philip Thomas
    •  & Trevor G. Smart
  3. Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, UK

    • Andrew R. Calver
    • , Warren D. Hirst
    • , Menelas N. Pangalos
    •  & Frank S. Walsh

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The authors declare no competing financial interests.

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Correspondence to Stephen J. Moss.

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DOI

https://doi.org/10.1038/nn833

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