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Adjacent phosphorylation sites on GABAA receptor β subunits determine regulation by cAMP-dependent protein kinase

Nature Neuroscience volume 1, pages 23–28 (1998)Cite this article

Abstract

Activation of cAMP-dependent protein kinase (PKA) can enhance or reduce the function of neuronal GABAA receptors, the major sites of fast synaptic inhibition in the brain. This differential regulation depends on PKA-induced phosphorylation of adjacent conserved sites in the receptor β subunits. Phosphorylation of β3 subunit-containing receptors at S408 and S409 enhanced the GABA-activated response, whereas selectively mutating S408 to alanine converted the potentiation into an inhibition, comparable to that of β1 subunits, which are phosphorylated solely on S409. These distinct modes of regulation were interconvertible between β1 and β3 subunits and depended upon the presence of S408 in either subunit. In contrast, β2 subunit-containing receptors were not phosphorylated or affected by PKA. Differential regulation by PKA of postsynaptic GABAA receptors containing different β subunits may have profound effects on neuronal excitability.

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Figure 1: Phosphorylation by PKA of β2 and β3 subunits in recombinant murine GABAA receptors.
Figure 2: Functional regulation of recombinant murine GABAA receptors containing β2 or β3 subunits by PKA-induced phosphorylation.
Figure 3: Mutation of serines 408 and 409 within the β3 subunit affects the regulation of GABAA receptor function by PKA-induced phosphorylation.
Figure 4: Phosphorylation by PKA of β1(A408S) and β1(A408S,S409A) subunits and the functional regulation of recombinant murine GABAA receptors.

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Acknowledgements

This work was supported by the Medical Research Council, Wellcome Trust and The Royal Society. We thank Alastair Hosie and Philip Thomas for comments.

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Author notes

  1. B. J. M., A. A. and S. J. M. contributed equally to this work.

  2. Request for materials should be addressed to S. J. M.

Authors and Affiliations

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

    Bernard J. McDonald, Christopher N. Connolly & Stephen J. Moss

  2. Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK

    Alessandra Amato & Trevor G. Smart

  3. Institute of Pharmacology, University of Zurich, Winterthurerstrasse 190, Zurich, 8057, Switzerland

    Dietmar Benke

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  1. Bernard J. McDonald
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Correspondence to Trevor G. Smart.

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McDonald, B., Amato, A., Connolly, C. et al. Adjacent phosphorylation sites on GABAA receptor β subunits determine regulation by cAMP-dependent protein kinase. Nat Neurosci 1, 23–28 (1998). https://doi.org/10.1038/223

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