cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors.
Chronic activity blockade increases synaptic levels of NMDA receptor immunoreactivity in hippocampal neurons. We show here that blockade-induced synaptic NMDA receptors are functional and mediate enhanced excitotoxicity in response to synaptically released glutamate. Activity blockade increased the cell surface association of NMDA receptors. Blockade-induced synaptic targeting of NMDA receptors did not require protein synthesis but required phosphorylation and specifically cAMP-dependent protein kinase (PKA). Furthermore, activation of PKA was sufficient to induce synaptic targeting of NMDA receptors regardless of receptor activity status. These results implicate PKA activity downstream of receptor blockade as a mediator of enhanced synaptic transport or stabilization of NMDA receptors. Synaptic clustering of NR1-green fluorescent protein was observed in living neurons in response to NMDA receptor and cAMP phosphodiesterase antagonists and occurred gradually over the course of a day. This pathway represents a cellular mechanism for synaptic homeostasis and is likely to function in metaplasticity, long-term regulation of the ability of a synapse to undergo potentiation or depression.
Crump
F T
FT
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Dillman
K S
KS
Craig
A M
AM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006624:Hippocampus; D008164:Luminescent Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors; D051381:Rats; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D016708:Synaptophysin; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases