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Nat Neurosci. 2014 Jul;17(7):914-22. doi: 10.1038/nn.3724. Epub 2014 May 25.

Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents.

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1] Graduate Program in Neuroscience, Stony Brook University, Stony Brook, New York, USA. [2] Medical Scientist Training Program, Stony Brook University, Stony Brook, New York, USA.
Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
1] Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York, USA. [2] Center for Nervous System Disorders, Stony Brook University, Stony Brook, New York, USA.


The fidelity of integration of pre- and postsynaptic activity by NMDA receptors (NMDARs) requires a match between agonist binding and ion channel opening. To address how agonist binding is transduced into pore opening in NMDARs, we manipulated the coupling between the ligand-binding domain (LBD) and the ion channel by inserting residues in a linker between them. We found that a single residue insertion markedly attenuated the ability of NMDARs to convert a glutamate transient into a functional response. This was largely a result of a decreased likelihood of the channel opening and remaining open. Computational and thermodynamic analyses suggest that insertions prevent the agonist-bound LBD from effectively pulling on pore lining elements, thereby destabilizing pore opening. Furthermore, this pulling energy was more prominent in the GluN2 subunit. We conclude that an efficient NMDAR-mediated synaptic response relies on a mechanical coupling between the LBD and the ion channel.

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