NMDA Receptor Transmembrane Domain: Structure and Mechanism of Ion Selectivity

Abstract

NMDA receptors (NMDARs) are iGluR subfamilies that are activated during synaptic transmission. The voltage dependence of NMDARs differentiates them from other iGluRs: at typical neuronal resting voltages, NMDAR channels are mostly blocked by Mg2+, but when membrane voltage is depolarized, Mg2+ block is relieved, resulting in Ca2+ influx through NMDAR at postsynaptic sites. The mechanisms, by which NMDARs select Ca2+ for permeation over all other physiological ions, while binding Mg2+ and restricting its permeation, are not well understood.Recently, partially resolved medium-resolution structures of an NMDAR tetramer were published. The structures tremendously improve our knowledge and understanding of the architecture and design of the NMDARs. Yet, one of the key structural features, namely the ion selectivity filter and parts of the pore region of the ion channel itself, are missing from these structures. This region of the protein has not been resolved also in the earlier high-resolution structure of an AMPAR, a closely related iGluR family member.Previously a successful homology model of the NMDAR TMD using one of the potassium channel family members, NaK channel as a template, was shown to have good agreements with available experimental data [Siegler et. al., Nat Neurosci 15: 406–13]. Given recently released NMDAR structures and our previously developed homology model, we are now in position to propose a high resolution NMDAR TMD model that is based on a hybrid structure. We performed extensive molecular dynamics (MD) and targeted MD simulations of our NMDAR TMD domain model in lipid bilayer and water. We demonstrate that our proposed structure is stable in simulations and has a well-formed binding site for Mg2+ and Ca2+.