NMDA receptor

The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA is a name of its selective specific agonist). NMDARs play a critical role in synaptic plasticity mechanisms and thus are necessary for several types of learning and memory.

Contents

1 Structure 2 Agonists 3 Modulators 4 Role 5 See also 6 External links

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 disinct 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 agonit-binding module links to a membrane domain which consists of three trans-membrane segments and a re-entrant loop reminescent of the selectivity filter of potassium channels. The membrane domain conributes 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 interract with a large number of structural,adaptor and scaffolding proteins. The glycine-binding module of the NR1 subunit has been expresed as a soluble protein and its three-dimensional structure has been solved at atomic resolution by X-ray christalography. It has revealed a common fold with aminoacid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors.

Agonists

A unique feature of NMDA receptor is the requirement for both glutamate and the co-agonist glycine for the efficient opening of the ion channel which is a part of this receptor.

A third requirement is membrane depolarization. A change in electrical potential toward equilibrium between the two sides of the membrane in which the receptor sits 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, which states that "Neurons that fire together, wire together".

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. regulated by ion channels that are permeable to Ca²⁺, Na⁺, K⁺ and are sensitive to voltage-dependent Mg²⁺ block.

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 wide range of physiologic and pathologic processes.

See also

• Category: NMDA receptor antagonists (http://en.wikipedia.org/wiki/Category:NMDA_receptor_antagonists)

External links

• Liu Y, Zhang J., 2000 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11775847&dopt=Abstract)
• Dingledine R et al. 1999, The Glutamate Receptor Ion Channels Pharmacological Reviews (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10049997) Authoritative, free review article.
• NMDA receptor pharmacology (http://www.bris.ac.uk/Depts/Synaptic/info/pharmacology/NMDA.html)de:NMDA-Rezeptor