Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors
Copyright policy )Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors
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 β-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.
- Vanderbilt University United States
Male, Adrenergic beta-Antagonists, Calcineurin Inhibitors, Long-Term Potentiation, Isoproterenol, Glutamic Acid, Benzothiadiazines, Cyclic AMP-Dependent Protein Kinases, Hippocampus, Mice, Inbred C57BL, Mice, 2-Amino-5-phosphonovalerate, Cyclic AMP, Cyclosporine, GTP-Binding Protein alpha Subunits, Gs, Animals, Calcium, Marine Toxins, Egtazic Acid, Excitatory Amino Acid Antagonists
Male, Adrenergic beta-Antagonists, Calcineurin Inhibitors, Long-Term Potentiation, Isoproterenol, Glutamic Acid, Benzothiadiazines, Cyclic AMP-Dependent Protein Kinases, Hippocampus, Mice, Inbred C57BL, Mice, 2-Amino-5-phosphonovalerate, Cyclic AMP, Cyclosporine, GTP-Binding Protein alpha Subunits, Gs, Animals, Calcium, Marine Toxins, Egtazic Acid, Excitatory Amino Acid Antagonists
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