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The Journal of Neuroscience, February 20, 2008, 28(8):1865-1870; doi:10.1523/JNEUROSCI.5417-07.2008

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Cellular/Molecular
Ca²⁺/CaM Controls Ca²⁺-Dependent Inactivation of NMDA Receptors by Dimerizing the NR1 C Termini

Chaojian Wang,¹ Hong-Gang Wang,¹ Hui Xie,² and Geoffrey S. Pitt¹

¹Department of Medicine, Duke University, Durham, North Carolina 27710, and ²Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032

Correspondence should be addressed to Geoffrey S. Pitt, Department of Medicine, Box 103030, Medical Center, Duke University, Durham, NC 27710. Email: geoffrey.pitt{at}duke.edu

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 -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, -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, -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.

Key words: calcium; calmodulin; channel; glutamate; inactivation; NMDA receptors

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Received June 14, 2007; revised Jan. 7, 2008; accepted Jan. 8, 2008.

Correspondence should be addressed to Geoffrey S. Pitt, Department of Medicine, Box 103030, Medical Center, Duke University, Durham, NC 27710. Email: geoffrey.pitt{at}duke.edu

This article has been cited by other articles:

				O. Cauli, R. Rodrigo, J. Boix, B. Piedrafita, A. Agusti, and V. Felipo Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain Am J Physiol Gastrointest Liver Physiol, September 1, 2008; 295(3): G503 - G511. [Abstract] [Full Text] [PDF]

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