Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors

NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glu...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2021-01, Vol.118 (2), p.1-10
Hauptverfasser: Iacobucci, Gary J., Wen, Han, Helou, Matthew, Liu, Beiying, Zheng, Wenjun, Popescu, Gabriela K.
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Iacobucci, Gary J.
Wen, Han
Helou, Matthew
Liu, Beiying
Zheng, Wenjun
Popescu, Gabriela K.
description NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glutamate binding to glycine-bound receptors and subsequent constriction of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical pulling on transmembrane helices. Here, we used molecular and kinetic simulations and double-mutant cycle analyses to show that a direct chemical interaction between GluN1-I642 (on M3 helix) and GluN2A-L550 (on L1-M1 linker) stabilizes receptors after they have opened and thus represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence causes deficits in charge transfer by GluN1-I642L, a pathogenic human variant.
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subjects Binding
Biological Sciences
Channel gating
Charge transfer
Glutamic acid receptors (ionotropic)
Glycine
Helices
Humans
Kinetics
Molecular Dynamics Simulation
N-Methyl-D-aspartic acid receptors
Receptors
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Synapses
title Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors
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