Brandon, N.J., Jovanovic, J.N., Smart, T.G. and Moss, S.J. (2002) 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. Journal of Neuroscience, 22 (15). pp. 6353-6361.
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Official URL: http://www.jneurosci.org/content/22/15/6353.full.pdf
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: alpha(1-6), beta(1-3), gamma(1-3), delta(1), epsilon, theta;, and pi, but the majority of receptor subtypes is believed, however, to be composed of alpha, beta, and gamma2 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 beta subunits. Although RACK-1 is not essential for PKC binding to GABA(A) receptor beta subunits, it enhances the phosphorylation of serine 409, a residue critical for the phospho-dependent modulation of GABA(A) receptor function in the beta1 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 beta 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.
|Departments, units and centres:||Department of Pharmacology > Department of Pharmacology|
|Journal or Publication Title:||Journal of Neuroscience|
|Deposited By:||Library Staff|
|Deposited On:||07 Apr 2011 11:23|
|Last Modified:||07 Apr 2011 11:33|
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