ro-25-6981 and cyclothiazide

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.

Topics: 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; Marine Toxins; 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