Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II.
In contrast to the rapid regulation of AMPA receptors, previous evidence has supported the idea that the synaptic density of NMDA-type glutamate receptors is fairly static, modulated only over a long time scale in a homeostatic manner. We report here that selective activation of protein kinase C (PKC) with phorbol esters induces a rapid dispersal of NMDA receptors from synaptic to extrasynaptic plasma membrane in cultured rat hippocampal neurons. PKC activation induced a simultaneous translocation of calcium/calmodulin-dependent kinase II (CaMKII) to synapses but no change in spine number, presynaptic terminal number, or the distribution of AMPA receptors or the synaptic scaffolding protein PSD-95. PKC-induced accumulation of CaMKII was dependent on filamentous actin, whereas dispersal of NMDA receptors occurred by a different mechanism independent of actin or CaMKII. Consistent with the decrease in synaptic density of NMDA receptors, phorbol ester pretreatment reduced excitotoxicity. These results reveal a surprisingly dynamic nature to the molecular composition and functional properties of glutamatergic postsynaptic specializations.
Fong
Dan K
DK
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Rao
Anuradha
A
Crump
F Thomas
FT
Craig
Ann Marie
AM
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D013997:Time Factors
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins; D049452:Green Fluorescent Proteins; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases