Ca2+/CaM controls Ca2+-dependent inactivation of NMDA receptors by dimerizing the NR1 C termini.
Ca2+ influx through NMDA receptors (NMDARs) leads to channel inactivation, which limits Ca2+ entry and protects against excitotoxicity. Extensive functional data suggests that this Ca2+-dependent inactivation (CDI) requires both calmodulin (CaM) binding to the C0 cassette of the NR1 subunit's C terminus (CT) and regulation by alpha-actinin-2, but a molecular understanding of CDI has been elusive. Here we used a number of methods to analyze the molecular nature of the interaction among CaM, alpha-actinin-2, and the NR1 CT. We found that a single CaM binds to two NR1 CTs in a Ca2+-dependent manner and promotes their reversible "dimerization." Expressed NMDARs containing NR1 concatamers in which the NR1 C termini are "uncoupled" display markedly reduced CDI. In contrast to current models, alpha-actinin-2 does not bind to the NR1 CT. We propose a new model for CDI in which the noncanonical Ca2+/CaM-dependent dimerization of the two NR1 subunits inactivates the channel by propagating a conformational change from the short NR1 CT to the nearby channel pore.
Wang
Chaojian
C
Department of Medicine, Duke University, Durham, North Carolina 27710, USA.
Wang
Hong-Gang
HG
Xie
Hui
H
Pitt
Geoffrey S
GS
D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
D002147:Calmodulin; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium