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The Journal of Neuroscience, August 1, 2002, 22(15):6353-6361

Receptor for Activated C Kinase-1 Facilitates Protein Kinase C-Dependent Phosphorylation and Functional Modulation of GABA_A Receptors with the Activation of G-Protein-Coupled Receptors

Nicholas J. Brandon¹, Jasmina N. Jovanovic¹, Trevor G. Smart², 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, and ² Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, United Kingdom

GABA_A receptors are the principal sites of fast synaptic inhibition in the brain. These receptors are hetero-pentamers that can be assembled from a number of subunit classes: (1-6), (1-3), (1-3), (1), , , and , but the majority of receptor subtypes is believed, however, to be composed of , , and 2 subunits. A major mechanism for modulating GABA_A receptor function occurs via the phosphorylation of residues within the intracellular domains of receptor subunits by a range of serine/threonine and tyrosine kinases. However, how protein kinases are targeted to these receptors to facilitate functional modulation remains unknown. Here we demonstrate that the receptor for activated C kinase (RACK-1) and protein kinase C (PKC) bind to distinct sites on GABA_A receptor  subunits. Although RACK-1 is not essential for PKC binding to GABA_A receptor  subunits, it enhances the phosphorylation of serine 409, a residue critical for the phospho-dependent modulation of GABA_A receptor function in the 1 subunit by anchored PKC. Furthermore, RACK-1 also enhances GABA_A receptor functional modulation in neurons by a PKC-dependent signaling pathway with the activation of muscarinic acetylcholine receptors (mAChRs). This PKC-dependent modulation of neuronal GABA_A receptors was mirrored by an increase in the phosphorylation of GABA_A receptor  subunits with the activation of mAChRs.

Our results suggest a central role for RACK-1 in potentiating PKC-dependent phosphorylation and functional modulation of GABA_A receptors. Therefore, RACK-1 will enhance functional cross talk between GABA_A receptors and G-protein-coupled receptors and therefore may have profound effects on neuronal excitability.

Key words: GABA_A receptor; protein kinase C; receptor for activated C kinase; muscarinic receptor phosphorylation; cross talk; GST fusion protein

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22156353-09$05.00/0

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