Novel blockade of protein kinase A-mediated phosphorylation of AMPA receptors.

Vanhoose AM, Clements JM, Winder DG
J Neurosci. 2006 26 (4): 1138-45

PMID: 16436600 · DOI:10.1523/JNEUROSCI.3572-05.2006

The phosphorylation state of the glutamate receptor subtype 1 (GluR1) subunit of the AMPA receptor (AMPAR) plays a critical role in synaptic expression of the receptor, channel properties, and synaptic plasticity. Several Gs-coupled receptors that couple to protein kinase A (PKA) readily recruit phosphorylation of GluR1 at S845. Conversely, activation of the ionotropic glutamate NMDA receptor (NMDAR) readily recruits dephosphorylation of the same GluR1 site through Ca2+-mediated recruitment of phosphatase activity. In a physiological setting, receptor activation often overlaps and crosstalk between coactivation of multiple signaling cascades can result in differential regulation of a given substrate. After investigating the effect of coactivation of the NMDAR and the Gs-coupled beta-adrenergic receptor on GluR1 phosphorylation state, we have observed a novel signal that prevents PKA-mediated phosphorylation of GluR1 at serine site 845. This blockade of GluR1 phosphorylation is dependent on cellular depolarization recruited by either NMDAR or AMPAR activation, independent of Ca2+ and independent of calcineurin, protein phosphatase 1, and/or protein phosphatase 2A activity. Thus, in addition to the typical kinase-phosphatase rivalry mediating protein phosphorylation state, we have identified a novel form of phospho-protein regulation that occurs at GluR1 and may also occur at several other PKA substrates.

MeSH Terms (34)

2-Amino-5-phosphonovalerate Adrenergic beta-Antagonists alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Animals Benzothiadiazines Calcineurin Inhibitors Calcium Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclosporine Egtazic Acid Excitatory Amino Acid Antagonists Glutamic Acid GTP-Binding Protein alpha Subunits, Gs Hippocampus Isoproterenol Long-Term Potentiation Male Mice Mice, Inbred C57BL N-Methylaspartate Oxazoles Phenols Phosphoprotein Phosphatases Phosphorylation Phosphoserine Piperidines Protein Phosphatase 1 Protein Phosphatase 2 Protein Processing, Post-Translational Receptors, Adrenergic, beta-1 Receptors, AMPA Receptors, N-Methyl-D-Aspartate Signal Transduction

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