NMDA-receptor

NMDA receptors (N-methyl-D-aspartate receptors - they are named after the also effective selective agonist N-methyl-D-aspartate) are ionotropic glutamate receptors. Ionotropic receptors activate membrane channels where ions can pass through when open. They differ from AMPA receptors in that they are permeable to calcium when activated. Their properties make them particularly important for learning and memory.

The ion channel of the NMDA receptor-channel complex is well permeable to Na+ , K+ and Ca2+ ions (Monaghan et al. 1989). Ca2+ ion influx triggers intracellular processes that appear to be responsible for both neuronal plasticity and NMDA receptor-mediated neurotoxicity (Hardingham and Bading 2003). The ion channel of the NMDA receptor is blocked in a voltage-dependent manner by Mg2+ ions (Nowak et al.1984). This blocking is released when the resting membrane potential of the neuron becomes more positive than -20 to -30 mV (Mayer et al.1984). Another characteristic of the NMDA receptor is the slow time course of the excitatory postsynaptic currents (EPSC; Lester et al. 1990) mediated by it. The NMDA receptor is a protein composed of four different transmembrane subunits (Cull-Candy et al. 2001).

In the NMDA receptor-channel complex, there are various binding sites for ligands, some of which have only modulatory functions. The following binding sites are known (Monaghan et al. 1989; Dingledine et al. 1999):

• the agonist binding site formed by the NR2A-D subunit.
• the glycine binding site formed by the NR1 subunit
• a binding site for antagonists such as phenylcyclidine
• a voltage-dependent Mg2+ ion binding site, which also binds the NMDA receptor antagonist memantine
• a binding site for the Zn2+ ions which block the channel in a voltage-dependent manner
• a binding site for the modulatory polyamines spermine and spermidine
• a binding site for protons.

At many excitatory synapses, NMDA receptors are colocalized with AMPA receptors. Presynaptic release of glutamate can thus lead to AMPA receptor-mediated pre-depolarization of the postsynaptic cell. As a result, the Mg2+ block is released from the ion channel of the NMDA receptor, and NMDA receptor-mediated ionic currents can flow.

1. Cull-Candy S et al (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11: 327-335.
2. Dingledine R et al (1999) The glutamate receptor ion channels. Pharmacol Rev 51: 7-61.
3. Hardingham GE et al (2003) The yin and yang of NMDA receptor signalling. Trends Neurosci 26: 81-9.
4. Mayer ML et al (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309: 261-263.
5. Monaghan D T et al (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29: 365-402.
6. Nowak L et al (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307: 462-465.