Ca2+/CaM controls Ca2+-dependent inactivation of NMDA receptors by dimerizing the NR1 C termini.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wang, C; Wang, H-G; Xie, H; Pitt, GS

Published Date

  • February 20, 2008

Published In

Volume / Issue

  • 28 / 8

Start / End Page

  • 1865 - 1870

PubMed ID

  • 18287503

Pubmed Central ID

  • PMC6671448

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.5417-07.2008


  • eng

Conference Location

  • United States