page_title: NMDA receptor
section_title: Gating
hierarchical_section_title: NMDA receptor / Gating
context_page_description: The N-methyl-D-aspartate receptor, is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors. The other receptors are the AMPA and kainate receptors. It is activated when glutamate and glycine bind to it, and when activated it allows positively charged ions to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity and memory function.
  The NMDAR is a specific type of ionotropic glutamate receptor. The NMDA receptor is so named because the agonist molecule N-methyl-D-aspartate binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations, with a combined reversal potential near 0 mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage dependent. Extracellular magnesium and zinc ions can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel.
context_section_description: The NMDA receptor is a glutamate and ion channel protein receptor that is activated when glycine and glutamate bind to it. The receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits: GluN1, GluN2 and GluN3.  GluN1 has eight different isoforms due to alternative splicing of the gene GRIN1. There are four different GluN2 subunits (A-D) and two different Glun3 subunits (A and B). Six separate genes encode for GluN2 and GluN3. All the subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins. Figure 1 shows a basic structure of GluN1/GluN2 subunits that forms the binding site for memantine, Mg²⁺ and ketamine.
  Mg²⁺ blocks the NMDA receptor channel in a voltage-dependent manner. The channels are also highly permeable to Ca²⁺. Activation of the receptor depends on glutamate binding, D-serine or glycine binding at its GluN1-linked binding site  and  AMPA receptor-mediated depolarization of the postsynaptic membrane, which relieves the voltage-dependent channel block by Mg²⁺. Activation and opening of the receptor channel thus allows the flow of K⁺, Na⁺ and Ca²⁺ ions, and the influx of Ca²⁺ triggers intracellular signaling pathways. Allosteric receptor binding sites for zinc, proteins and the polyamines spermidine and spermine are also modulators for the NMDA receptor channels.
  The GluN2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangements. The basic structure and functions associated with the NMDA receptor can be attributed to the GluN2B subunit. For example, the glutamate binding site and the control of the Mg²⁺ block are formed by the GluN2B subunit. The high affinity sites for glycine antagonist are also exclusively displayed by the GluN1/GluN2B receptor.
  GluN1/GluN2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the GluNB subunit and A645 and N616 on the GluN1 subunit, are important for binding of memantine and related compounds as seen in figure 2.
  The NMDA receptor forms a heterotetramer between two GluN1 and two GluN2 subunits (the subunits were previously denoted as GluN1 and GluN2), two obligatory GluN1 subunits and two regionally localized GluN2 subunits. A related gene family of GluN3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the GluN1 transcripts and differential expression of the GluN2 subunits.
  Each receptor subunit has modular design and each structural module, also represents a functional unit:
  The extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain. GluN1 subunits bind the co-agonist glycine and GluN2 subunits bind the neurotransmitter glutamate.
  The agonist-binding module links to a membrane domain, which consists of three transmembrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels.
  The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block.
  Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural,
caption: Figure 1: NR1/NR2 NMDA receptor