NMDA receptor

The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel which is nonselective to cations. This allows flow of Na+ and K+ ions, and small amounts of Ca2+. Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is interesting in that is both ligand-gated but also voltage-dependent.

Structure
The structure of NMDA receptors at atomic resolution has been recently solved and reveals heterodimer formation between NR1 and NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A through 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 NR1 transcripts and differential expression of the NR2 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. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. The agonist-binding module links to a membrane domain which consists of three trans-membrane 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. Lastly, 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 which interact with a large number of structural, adaptor and scaffolding proteins. The glycine-binding module of the NR1 subunit and the glutamate-binding module of the NR2A subunit have been expressed as a soluble proteins and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.

Various isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A through D. They contain the binding-site for the neurotransmitter glutamate. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil.

Agonists
Activation of NMDA receptors requires binding of both glutamate and the co-agonist glycine for the efficient opening of the ion channel which is a part of this receptor. In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

Antagonists
Synthetic antagonists include:
 * Amantadine
 * AP5 (2-amino-5-phosphonopentanoate), a competitive glutamate antagonist selective for the NMDA-R.
 * Dextrorphan
 * Ketamine
 * Memantine (Axura®, Akatinol®, Namenda®, Ebixa®)
 * MK-801 (dizocilpine)
 * Phencyclidine
 * Riluzole

All are non-competitive channel blockers.

Additionally, drugs can act at the glycine binding site, as does 7-chlorokynurenate.

Modulators
The NMDA receptor is modulated by a number of endogenous and exogenous compounds. Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium treatment has been used to produce rapid recovery from depression. Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Zn2+ blocks the NMDA current in a noncompetitive and a voltage-independent manner. It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses. The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions.

Role
This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. NMDA receptors play a key role in a wide range of physiologic and pathologic processes.