Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents

The fidelity of NMDA receptors (NMDARs) to integrate pre- and post-synaptic activity 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 find that a single residue insertion dramatically attenuates the ability of NMDARs to convert a glutamate transient into a functional response. This is largely due to a decreased likelihood for the channel to open and remain open. Computational and thermodynamic analyses suggest that insertions prevent the agonist-bound LBD from effectively pulling on pore lining elements, thereby destabilizing pore opening. Further, this pulling energy is 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.