CALMODULIN MEDIATES CALCIUM-DEPENDENT INACTIVATION OF N-METHYL-D-ASPARTATE RECEPTORS

Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors activates si gnal transduction pathways critical for many forms of synaptic plastic ity in the brain. NMDA receptor-mediated Ca2+ influx also downregulate s 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, sug gesting that carmodulin may play a role in CDI. We report here that th e mutation of a specific calmodulin binding site in the CO region of t he NR1 subunit of the NMDA receptor blocks CDI. Moreover, intracellula r infusion of a calmodulin inhibitory peptide markedly reduces CDI of both recombinant and neuronal NMDA receptors. Furthermore, this inacti vating 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 b inding of Ca2+/ calmodulin to NR1 mediates CDI of the NMDA receptor an d suggest that inactivation occurs via Ca2+/calmodulin-dependent relea se of the receptor complex from the neuronal cytoskeleton.