• calmodulin;
  • CDKL5;
  • dendritic spines;
  • hippocampus;
  • PSD-95


Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca2+ influx via NMDA receptors. Here, we show that Ca2+/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1–16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca2+-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca2+-induced dissociation of PSD-95 from the postsynaptic membrane.


Thumbnail image of graphical abstract

Ca2+ influx promotes Ca2+/calmodulin binding to the N-terminus of PSD-95, which blocks PSD-95 palmitoylation leading to reduced retention of PSD-95 at synapses. This effect will likely decrease postsynaptic glutamate receptor content and thereby synaptic strength.

  • Ca2+/calmodulin forms a collapsed structure around the N-terminal helix of PSD-95 that sequesters the palmitoylation sites (Cys3 and Cys5) and a key tyrosine (Tyr12).
  • Binding of Ca2+/calmodulin to the N-terminus of PSD-95 decreases its palmitoylation to release PSD-95 from postsynaptic sites
  • Binding of Ca2+/calmodulin also displaces the serine/threonine kinase CDKL5 from PSD-95, which otherwise helps augment synaptic strength
  • A point mutation of PSD-95 that prevents Ca2+/calmodulin binding turns the Ca2+-induced reduction in PSD-95 at synapses into an increase, uncovering the existence of a second mechanism that augments postsynaptic PSD-95 enrichment upon Ca2+ influx.