title: Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents.
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.
authors.affiliation: 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.
authors.forename: Rashek
authors.initials: R
authors.lastname: Kazi
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.affiliation: 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.
authors.forename: Cameron
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Wollmuth
mesh_terms: D000818:Animals; D003198:Computer Simulation; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D013816:Thermodynamics
chemical_list: D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate