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 permeable to Ca++, Na+ and K+ ions. 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. Ionotropic receptor (also ligand gated ion channel) are a subclass of transmembrane receptors. ... Glutamate is the anion of glutamic acid. ... NMDA (N-methyl-D-aspartic acid) is an amino acid derivative acting as specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... Another, unrelated ion channeling process is part of ion implantation. ... The term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse. ... Learned redirects here. ... Memory is a function of the brain: the ability to retain information. ...

Structure

The structure of NMDA receptors at atomic resolution remains unknown. Still, it is widely accepted that NMDA receptors assemble as hetero-tetramers of two obligatory NR1 subunits and two regionally localized NR2 subunits. Like-subunits have a vicinal arrangement. A related gene family of NR3 A-C subunits can substitute for NR2 subunits in specific brain regions and has 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 has been expressed as a soluble protein and its three-dimensional structure has been solved at atomic resolution by x-ray crystallography. It has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors. Properties For alternative meanings see atom (disambiguation). ... A tetramer is a protein with four subunits (tetrameric). ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... In biology, a protein isoform is a version of a protein with some small differences, usually a splice variant or the product of some posttranslational modification. ... In cell biology, molecular biology and related fields, the word extracellular means outside the cell. It is used in contrast to intracellular (inside the cell). ... Domain has several meanings (see subsections below for computer-related and mathematical senses): some kind of territory, such as (for example) a demesne or a realm In New Zealand a Town Domain is typically a public sport area administered by a Domain Board. ... In chemistry, a ligand is an atom, ion or functional group that is bonded to one or more central atoms or ions, usually metals generally through co-ordinate covalent bond. ... Domain has several meanings (see subsections below for computer-related and mathematical senses): some kind of territory, such as (for example) a demesne or a realm In New Zealand a Town Domain is typically a public sport area administered by a Domain Board. ... In cell biology, potassium channels are the most common type of ion channel. ... A pore, in general, is some form of opening, usually very small. ... Conductance can refer to: Electrical conductance, the reciprocal of electrical resistance. ... Permeability has several meanings: In electromagnetism, permeability is the degree of magnetisation of a material in response to a magnetic field. ... A protein kinase is an enzyme that can transfer a phosphate group from a donor molecule (usually ATP) to an amino acid residue of a protein. ... Protein phosphatases are enzymes that remove phosphate groups that have been attached to amino acid residues of proteins by protein kinases. ...

Varous isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A-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. Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. ... Glutamate is the anion of glutamic acid. ...

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. Glutamate is the anion of glutamic acid. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... This is an article about Glycine, the amino acid. ... In membrane biophysics sometimes used interchangeably with cell potential, but applicable to any lipid bilayer or membrane. ... Magnesium ions (Mg2+) in cellular biology are usually in almost all senses opposite to Ca2+ ions, because they are bivalent too, but have larger atomic radius. ... Memory is a function of the brain: the ability to retain information. ... Learned redirects here. ... Hebbian learning is a hypothesis for how neuronal connections are enforced in mammalian brains; it is also a technique for weight selection in artificial neural networks. ...

Antagonists

Synthetic antagonists include:

• AP5 (2-amino-5-phosphonopentanoate), a competitive glutamate antagonist selective for the NMDA-R.

• Ketamine
• MK-801 (dizocilpine)
• Dextromethorphan
• Phencyclidine, all of which are non-competitive channel blockers.

Additionally, drugs can act at the glycine binding site, as does 7-chlorokynurenate. APV chemical structure APV (also called AP5) is a selective NMDA receptor (NMDAR) antagonist that competitively inhibits the active site of NMDAR. Its chemical name is 2_amino_5_phosphonovalerate. ... Ketamine is a general dissociative anaesthetic for human and veterinary use. ... Dizocilpine (also known as MK-801) is a non-competitive NMDA receptor antagonist. ... Dextromethorphan hydrobromide monohydrate (DM or DXM) is an antitussive drug that is found in many over-the-counter cold and cough preparations. ... Phencyclidine (also called PCP, sherm, angel dust, Wet or Ashy Larry) is a dissociative psychedelic drug formerly used as an anaesthetic agent. ...

Modulators

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. 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. In an economic model, an endogenous change is one that comes from inside the model and is explained by the model itself. ... Exogenous (or exogeneous) (from the Greek words exo and gen, meaning outside and production) refers to an action or object coming from outside a system. ... Magnesium ions (Mg2+) in cellular biology are usually in almost all senses opposite to Ca2+ ions, because they are bivalent too, but have larger atomic radius. ... Membrane potential (or transmembrane potential or transmembrane potential difference or transmembrane potential gradient), is the electrical potential difference across a cells plasma membrane. ... Potassium is the main intracellular ion for all types of cells. ... Calcium plays a vital role in the biochemistry of the cell, particularly in signal transduction pathways. ... The polyamines are organic compounds, such as putrescine, spermidine, and spermine, that are growth factors in both eucaryotic and procaryotic cells. ...

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. Synapses allow nerve cells to communicate with one another through axons and dendrites, converting electrical signals into chemical ones. ... In the anatomy of animals, the brain, or encephalon, is the supervisory center of the nervous system. ... The spinal cord is a part of the vertebrate nervous system that is enclosed in and protected by the vertebral column (it passes through the spinal canal). ... Physiology (in Greek physis = nature and logos = word) is the study of the mechanical, physical, and biochemical functions of living organisms. ... Pathology (in ancient Greek pathos = feeling, pain, suffering and logos = discourse or treatise, i. ...

See also

• Category: NMDA receptor antagonists

External links

• Liu Y, Zhang J., 2000
• Dingledine R et al. 1999, The Glutamate Receptor Ion Channels Pharmacological Reviews Authoritative, free review article.
• NMDA receptor pharmacology