Mechanical Coupling Maintains the Fidelity of NMDA Receptor-mediated Currents

Overview

Journal Nat Neurosci

Date 2014 May 27

PMID 24859202

Citations 69

Authors

Rashek Kazi

Jian Dai

Cameron Sweeney

Huan-Xiang Zhou

Lonnie P Wollmuth

Affiliations

Soon will be listed here.

Abstract

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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