cAMP-dependent protein kinase postsynaptic localization regulated by NMDA receptor activation through translocation of an A-kinase anchoring protein scaffold protein.
NMDA receptor-dependent long-term potentiation and long-term depression (LTD) involve changes in AMPA receptor activity and postsynaptic localization that are in part controlled by glutamate receptor 1 (GluR1) subunit phosphorylation. The scaffolding molecule A-kinase anchoring protein (AKAP)79/150 targets both the cAMP-dependent protein kinase (PKA) and protein phosphatase 2B/calcineurin (PP2B/CaN) to AMPA receptors to regulate GluR1 phosphorylation. Here, we report that brief NMDA receptor activation leads to persistent redistribution of AKAP79/150 and PKA-RII, but not PP2B/CaN, from postsynaptic membranes to the cytoplasm in hippocampal slices. Similar to LTD, AKAP79/150 redistribution requires PP2B/CaN activation and is accompanied by GluR1 dephosphorylation and internalization. Using fluorescence resonance energy transfer microscopy in hippocampal neurons, we demonstrate that PKA anchoring to AKAP79/150 is required for NMDA receptor regulation of PKA-RII localization and that movement of AKAP-PKA complexes underlies PKA redistribution. These findings suggest that LTD involves removal of AKAP79/150 and PKA from synapses in addition to activation of PP2B/CaN. Movement of AKAP79/150-PKA complexes from the synapse could further favor the actions of phosphatases in maintaining dephosphorylation of postsynaptic substrates, such as GluR1, that are important for LTD induction and expression. In addition, our observations demonstrate that AKAPs serve not solely as stationary anchors in cells but also as dynamic signaling components.
Smith
Karen E
KE
Department of Pharmacology, University of Colorado at Denver, Health Sciences Center, Aurora, Colorado 80045, USA.
Gibson
Emily S
ES
Dell'Acqua
Mark L
ML
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D004789:Enzyme Activation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016296:Mutagenesis; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; D001426:Bacterial Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C054562:yellow fluorescent protein, Bacteria; D012694:Serine; D016202:N-Methylaspartate; C056639:2-amino-5-phosphopentanoic acid; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D014633:Valine