NMDA Receptors
Glutamate and Aspartate

Author: Fabio Baraldo
Date: 15/09/2011

Description

DEFINITION

The NMDA Receptor is a specific type of ionotropic glutamate receptor. The name comes from a selective agonist that binds to NMDA receptors but not to the other Glutamate receptors, the agonist’s name is NMDA (N-Methyl-D-Aspartate).
The receptor is an ion channel which allows the flow of Na+ and Ca2+ into the cell and K+ out of the cell.

THE GENE

The NMDA receptor is an heterotetramer formed by two NR1 subunits and two NR2 subunits.
There are eight variants of NR1 subunits produced by alternative splicing of the gene called GRIN1.
There are four isoforms of the NR2 subunit in humans:
- NR2A produced by GRIN2A
- NR2B produced by GRIN2B
- NR2C produced by GRIN2C
- NR2D produced by GRIN2D

CHEMICAL STRUCTURE

Each of the subunit has an extracellular N-terminus, intracellular C-terminus and a re-entrant transmembrane domain.
The NMDA receptor is formed by four subunits:

  • Two NR1 subunits which are the essential components of the receptor.
  • Two NR2 subunits which are regionally localized.
    The combining of these different subunits allows to create a channel throughout the cellular membrane and to generate a large number of different NMDA recepetors.

Subunit NR1 aminoacids percentage:

Aminoacids percentage in the four isoforms of the NR2 subunit:

SYNTHESIS AND TURNOVER

In addition to the variability of the NR2 subunits, the NR1 subunit exists as multiple splice variants, produced by differential splicing of the mRNA derived from the GRIN1 gene.

There are two main sites for the splicing, as shown in the picture:
- N-terminus
- C-terminus

The eight NR1 variants produced by splicing are:
- NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form
- NR1-2a, NR1-2b;
- NR1-3a, NR1-3b;
- NR1-4a, NR1-4b;

CELLULAR FUNCTIONS

NMDA receptor is a channel which is normally closed at the resting membrane potential; it is both ligand-gated and voltage-dependent.
To be opened it must bind to Glutamate on the NR2 subunits and to Glycine on the NR1 subunits; thus the Glycine works as a Glutamate co-agonist in the activation of the receptors.
The binding of the two agonists does not open the channel due to the presence of an ion of Mg2+ which still blocks the flow of cations throughtout the channel. Cellular depolarization is needed to remove the Mg2+.
The opened channel allows Na+ and Ca2+ to flow into the cell and K+ out of the cell.
Intracellular Ca2* is involved in various signaling pathways as a second messenger such as activation of protein kinases and phosporylating enzymes.
The NMDA receptor is the predominant molecular device for controlling synaptic plasticity and memory function.
NMDA receptor stimulation will also increase the production of spinal phospholipase and induce the production of nitric oxide synthetase. The prostaglandins and nitric oxide, which are subsequently produced and released into the extracellular milieu, can facilitate further release of excitatory amino acids and neuropeptides from primary afferent pain fibres.

LIGANDS

Agonists

  • Aminocyclopropanecarboxylic acid
  • D-Cycloserine
  • cis-2,3-Piperidinedicarboxylic acid
  • L- aspartate
  • Quinolinate
  • Homocysterate
  • D-serine
  • ACPL
  • L-alanine
  • D-serine

Antagonists

Common NMDA receptor antagonists include:

  • Amantadine
  • Ketamine
  • Phencyclidine
  • Nitrous oxide
  • Dextromethorphan
  • Memantine
  • Ethanol
  • Riluzol
  • Xenon

Dual opiods and NMDA antagonists:

  • Ketobemidone
  • Methadone
  • Tramadol
  • Ibogaine

Modulators

  • 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+ and Cu2+ generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity.

Created by Fabio Baraldo

Comments
2013-03-31T10:19:26 - Gianpiero Pescarmona

NMDA receptor

NMDA is an amino acid derivative acting as a specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA binds to and regulates the above receptor only, but not other glutamate receptors.

NMDA and

  • arginine (Na) and NOS
  • glutamine (Ca and Na) AND PROLIFERATION
Attachments
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NR1.png30638515/09/2011
NR2.png30638515/09/2011
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