February 3, 2009
NMDA Receptors
The main excitatory neurotransmitter in the central nervous system is glutamate, an ionic form of one of the 20 primary amino acids. Glutamate is the major endogenous agonist for many different receptors, meaning that lots of cells are sensitive to it in different ways.
The ionotropic glutamate receptors -- that is, those that are ion channels as well as receptors, able to change membrane ion permeability directly rather than acting through secondary messaging pathways -- can be further divided into three main groups by their sensitivity to the more specific (but non-physiological) ligands α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainic acid or kainate (KA), and N-methyl-D-aspartate (NMDA). Functionally, the distinction between the NMDA-sensitive and non-NMDA-sensitive receptors is probably most important, and for this reason AMPA and kainate receptors are often grouped together rather indiscriminately.
Loosely speaking, NMDA receptors are slower than AMPA/KA receptors, and in at least some cases mediate longer-term effects. Although they are nominally non-selective cation channels, they exhibit a disproportionately high permeability to calcium ions. Extracellular calcium is always present at much lower concentrations than sodium, so the latter tends to dominate the current flow, but many intercellular processes -- notably those controlling neurotransmitter release and the distribution of receptors -- are extraordinarily sensitive to calcium, so the NMDA receptor permeability can have large functional consequences.
NMDA receptors are characteristically blocked by magnesium ions unless the membrane is relatively depolarised. Since magnesium is always present under physiological conditions, this means that NMDA receptors are very seldom effectively open unless an action potential is being fired. NMDA receptors are thus very important coincidence detectors, allowing ions to flow only when two different types of event occur simultaneously: ligand binding (typically as a result of release from the axon terminal of an upstream neuron) and action potential firing (in the receptor's own cell). For this reason, NMDA receptors are popular in models of associative learning: their dependence on two different inputs
Although mainly thought of as existing post-synaptically, transducing anterograde excitatory signals, there is also evidence of presynaptic NMDA receptor localisation in some neurons. It is the latter that we are interested in for this project.
1 Interestingly, some taste buds have glutamate receptors, giving rise to the so-called "fifth taste" umami. These receptors are what give the flavour enhancing food additive monosodium glutamate its power.
2 In fact, there are at least three necessary inputs, since NMDA receptors also require the binding of another amino acid ligand, glycine or serine. However, this is pretty much always present at saturating levels in the vicinity of central neurons, so it doesn't normally have an effect on response.
Posted by matt at February 3, 2009 5:27 PM