Glutamate acts on both ionotropic and metabotropic receptors in the CNS (Figure1). There are three subtypes of ionotropic glutamate receptors, each named for its relatively specific agonist. These are the AMPA (α-amino-3-hydroxy 5-methylisoxazole-4-propionate), kainate (kainate is an acid isolated from seaweed), and NMDA (N-methyl-D-aspartate) receptors. Table 1 summarizes some of the major proper ties of these receptors. Ionotropic glutamate receptors are tetramers composed of different subunits whose helical domains span the membranes three times and a short sequence that forms the channel pore. Four AMPA (GluR1–GluR4), five kainate (GluR5–GluR7, KA1, KA2), and six NMDA (NR1, NR2A–NR2D) subunits have been identified, and each is coded by a different gene.
Fig1. Biochemical events at a glutamatergic synapse. Glutamate (Glu) released into the synaptic cleft by Ca2+-dependent exocytosis. Released Glu can act on ionotropic and G-protein–coupled receptors on the postsynaptic neuron. Synaptic transmission is terminated by the active transport of Glu via by a Na+-dependent glutamate transporters located on membranes of the presynaptic terminal [Gt(n)] and glia [Gt(g)]. In glia, Glu is converted to glutamine (Gln) by the enzyme glutamine synthetase; Gln then diffuses into the nerve terminal where it is hydrolyzed back to Glu by the enzyme glutaminase. In the nerve terminal, Glu is highly concentrated in synaptic vesicles by a vesicular glutamate transporter.
Table1. Pharmacology of a selection of receptors for some small-molecule neurotransmitters.
The release of glutamate and its binding to AMPA or kainate receptors primarily permits the influx of Na+ and the efflux of K+, accounting for fast excitatory postsynaptic potential (EPSP). Most AMPA receptors have low Ca2+ permeability, but the absence of certain subunits in the receptor complex at some sites allows for the influx of Ca2+, which may contribute to the excitotoxic effect of glutamate.
Activation of the NMDA receptor permits the influx of relatively large amounts of Ca2+ along with Na+. When glutamate is in excess in the synaptic cleft, the NMDA receptor induced influx of Ca2+ into neurons is the major basis for the excitotoxic actions of glutamate. The NMDA receptor is unique in several ways (Figure 2). First, glycine facilitates its function by binding to the receptor. In fact, glycine binding is essential for the receptor to respond to glutamate. Second, when glutamate binds to the NMDA receptor, it opens, but at normal membrane potentials, the channel is blocked by extracellular Mg2+. This block is removed only when the neuron containing the receptor is partially depolarized by the activation of adjacent AMPA and kainate receptors. Third, the excitatory postsynaptic potential induced by activation of NMDA receptors is slower than that elicited by activation of the AMPA and kainate receptors.
Fig2. Diagrammatic representation of the NMDA receptor. When glycine and glutamate bind to the receptor, the closed ion channel (left) opens, but at the resting membrane potential, the channel is blocked by Mg2+ (right). This block is removed if partial depolarization is produced by other inputs to the neuron containing the receptor, and Ca2+ and Na+ enter the neuron. Blockade can also be produced by the drug dizocilpine maleate (MK-801).
Essentially all neurons in the CNS have both AMPA and NMDA receptors. Kainate receptors are located presynaptically on GABA-secreting nerve endings and postsynaptically at various sites, most notably in the hippocampus, cerebellum, and spinal cord. Kainate and AMPA receptors are found in glia as well as neurons, but NMDA receptors occur only in neurons. The concentration of NMDA receptors in the hippo campus is high, and blockade of these receptors prevents long term potentiation, a long-lasting facilitation of transmission in neural pathways following a brief period of high-frequency stimulation. Thus, these receptors may well be involved in memory and learning.
Activation of the metabotropic glutamate receptors (mGluR) leads to either an increase in intracellular inositol 1,4,5-triphosphate (IP3 ) and diacylglycerol (DAG) levels or a decrease in intracellular cAMP levels (Table 1). There are eight known subtypes of mGluR. These receptors are located at both presynaptic (mGluR2-4, 6-8 ) and postsynaptic sites (mGluR1, 5 ), and they are widely distributed in the brain. They appear to be involved in the production of synaptic plasticity, particularly in the hippocampus and the cerebellum. Activation of presynaptic mGluR autoreceptors on neurons in the hippocampus limits the release of glutamate from these neurons. Knockout of the gene mGluR1 causes severe motor incoordination and deficits in spatial learning.
A characteristic of an excitatory synapse is the presence of a thickened area called a postsynaptic density (PSD) on the membrane of the postsynaptic neuron. This is a complex structure containing ionotropic glutamate receptors and signaling, scaffolding, and cytoskeletal proteins. The mGluR are located adjacent to the PSD.
