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The Journal of Neuroscience, November 1, 1999, 19(21):9228-9234

Subunit-Specific Association of Protein Kinase C and the Receptor for Activated C Kinase with GABA Type A Receptors

Nicholas J. Brandon¹, Julia M. Uren¹, Josef T. Kittler¹, Hongbing Wang², Richard Olsen², Peter J. Parker³, and Stephen J. Moss¹

¹ Medical Research Council Laboratory of Molecular Cell Biology and Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, ² Department of Pharmacology, University of California at Los Angeles School of Medicine, Los Angeles, California 90024, and ³ Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

GABA receptors (GABA_A) are the major sites of fast synaptic inhibition in the brain and can be assembled from five subunit classes: , , , , and . Receptor function can be regulated by direct phosphorylation of  and 2 subunits, but how kinases are targeted to GABA_A receptors is unknown. Here we show that protein kinase C-II (PKC-II) is capable of directly binding to the intracellular domain of the receptor 1 and 3 subunits, but not to those of the 1 or 2 subunits. Moreover, associating PKC-II is capable of specifically phosphorylating serine 409 in 1 subunit and serines 408/409 within the 3 subunit, key residues for modulating GABA_A receptor function. The receptor for activated C kinase (RACK-1) was found also to bind to the 1 subunit intracellular domain, but PKC binding appeared to be independent of this protein. Using immunoprecipitation, the association of PKC isoforms and RACK-1 with neuronal GABA_A receptors was seen. Furthermore, PKC isoforms associating with neuronal receptors were capable of phosphorylating the receptor 3 subunit.

Together, these observations suggest GABA_A receptors are intimately associated with PKC isoforms via a direct interaction with receptor  subunits. This interaction may serve to localize PKC activity to GABA_A receptors in neurons allowing the rapid regulation of receptor activity by cell-signaling pathways that modify PKC activity.

Key words: GABA_A receptor; subunit; PKC; RACK-1; intracellular domain; protein kinase C

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19219228-07$05.00/0

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