CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation

Nat Neurosci. 2021 Jun;24(6):777-785. doi: 10.1038/s41593-021-00843-3. Epub 2021 Apr 29.


Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca2+ is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca2+-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / analysis*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Enzyme Activation / physiology
  • Female
  • Liquid-Liquid Extraction / methods*
  • Male
  • Membrane Proteins / analysis*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / analysis
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / analysis
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Membrane Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2