Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors

Neuron. 1998 Aug;21(2):443-53. doi: 10.1016/s0896-6273(00)80553-x.


Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors activates signal transduction pathways critical for many forms of synaptic plasticity in the brain. NMDA receptor-mediated Ca2+ influx also downregulates the gating of NMDA channels through a process called Ca2+-dependent inactivation (CDI). Recent studies have demonstrated that the calcium binding protein calmodulin directly interacts with NMDA receptors, suggesting that calmodulin may play a role in CDI. We report here that the mutation of a specific calmodulin binding site in the CO region of the NR1 subunit of the NMDA receptor blocks CDI. Moreover, intracellular infusion of a calmodulin inhibitory peptide markedly reduces CDI of both recombinant and neuronal NMDA receptors. Furthermore, this inactivating effect of calmodulin can be prevented by coexpressing a region of the cytoskeletal protein alpha-actinin2 known to interact with the CO region of NR1. Taken together, these results demonstrate that the binding of Ca2+/calmodulin to NR1 mediates CDI of the NMDA receptor and suggest that inactivation occurs via Ca2+/calmodulin-dependent release of the receptor complex from the neuronal cytoskeleton.

MeSH terms

  • Actinin / analysis
  • Animals
  • Binding Sites
  • Calcium / physiology*
  • Calmodulin / physiology*
  • Cell Line
  • Down-Regulation
  • Feedback
  • Infusions, Parenteral
  • Ion Channel Gating
  • Mutagenesis, Site-Directed
  • Neuronal Plasticity / physiology*
  • Point Mutation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Signal Transduction / physiology*


  • Calmodulin
  • Receptors, N-Methyl-D-Aspartate
  • Actinin
  • Calcium