Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors.
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.
Zhang
S
S
Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Ehlers
M D
MD
Bernhardt
J P
JP
Su
C T
CT
Huganir
R L
RL
D000185:Actinin / Q000032:analysis; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D005246:Feedback; D007263:Infusions, Parenteral; D015640:Ion Channel Gating; D016297:Mutagenesis, Site-Directed; D009473:Neuronal Plasticity / Q000502:physiology*; D017354:Point Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*
D002147:Calmodulin; D016194:Receptors, N-Methyl-D-Aspartate; D000185:Actinin; D002118:Calcium