Interaction between αCaMKII and GluN2B controls ERK-dependent plasticity

J Neurosci. 2012 Aug 1;32(31):10767-79. doi: 10.1523/JNEUROSCI.5622-11.2012.


Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca(2+) concentration. However the mechanism by which a short-lasting rise in Ca(2+) concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca(2+) elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that αCaMKII, but not βCaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and αCaMKII. We then show that interfering with GluN2B/αCaMKII interaction prevents synaptic activity from inducing ERK-dependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and αCaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Analysis of Variance
  • Animals
  • Bicuculline / pharmacology
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Dendritic Spines / metabolism
  • Disks Large Homolog 4 Protein
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • Guanylate Kinases / metabolism
  • Immunoprecipitation
  • In Vitro Techniques
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MAP Kinase Signaling System / physiology*
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Photobleaching
  • Potassium Channel Blockers / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Transfection


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • GABA-A Receptor Antagonists
  • Luminescent Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • NR2B NMDA receptor
  • Potassium Channel Blockers
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • 4-Aminopyridine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Guanylate Kinases
  • Calcium
  • Bicuculline