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 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.
Vanhoose
Amanda M
AM
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.
Clements
Julie M
JM
Winder
Danny G
DG
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D015763:2-Amino-5-phosphonovalerate; D000319:Adrenergic beta-Antagonists; D001581:Benzothiadiazines; D065095:Calcineurin Inhibitors; D002118:Calcium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D016572:Cyclosporine; D004533:Egtazic Acid; D018691:Excitatory Amino Acid Antagonists; D019205:GTP-Binding Protein alpha Subunits, Gs; D018698:Glutamic Acid; D007545:Isoproterenol; D008387:Marine Toxins; D016202:N-Methylaspartate; D010080:Oxazoles; D010636:Phenols; D010749:Phosphoprotein Phosphatases; D010768:Phosphoserine; D010880:Piperidines; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D018091:Receptors, AMPA; D018342:Receptors, Adrenergic, beta-1; D016194:Receptors, N-Methyl-D-Aspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C121001:NR2B NMDA receptor; C109643:Ro 25-6981; C059041:calyculin A; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C004639:cyclothiazide