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

Su Zhang, Michael D. Ehlers, Jeffery P. Bernhardt, Ching Tien Su, Richard L. Huganir

Research output: Contribution to journalArticlepeer-review


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 α-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.

Original languageEnglish (US)
Pages (from-to)443-453
Number of pages11
Issue number2
StatePublished - Aug 1998

ASJC Scopus subject areas

  • Neuroscience(all)


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