NMDA receptors are as ubiquitous as AMPA receptors, being present on essentially all neurons in the CNS. All NMDA receptors require the presence of the subunit GluN1. The channel also contains one or two GluN2 subunits (GluN2A–GluN2D). Unlike AMPA and kainate receptors, all NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+. NMDA receptor function is controlled in a number of intriguing ways. In addition to glutamate binding, the channel also requires the binding of glycine to a separate site in order for the channel to open. However, the regulation and physiologic role of glycine binding remain unclear. Another important feature is that while AMPA and kainate receptor activation results in channel opening at resting membrane potential, NMDA receptor activation does not. This is because, at resting membrane potential, the NMDA receptor pore is blocked by extracellular Mg2+. Only when the neuron is strongly depolarized, as occurs with intense activation of the synapse or by activation of neighboring synapses, is the Mg2+ expelled, allowing the channel to open. Thus, there are three requirements for NMDA receptor channel opening: Glutamate and glycine must bind the receptor, and the membrane must be depolarized. The rise in intracellular Ca2+ that accompanies NMDA receptor channel opening results in a long-lasting enhancement in synaptic strength that is referred to as long-term potentiation (LTP). This enhancement of synaptic strength, which is one major type of synaptic plasticity, can last for many hours or even days and is generally accepted as an important cellular mechanism underlying learning and memory.
The metabotropic glutamate receptors are G protein-coupled receptors that act indirectly on ion channels via G proteins. Metabotropic receptors (mGluR1–mGluR8) have been divided into three groups (I, II, and III). A variety of agonists and antagonists have been developed that interact selectively with the different groups. Group I receptors are typically located postsynaptically and activate phospholipase C, leading to inositol trisphosphate-mediated intracellular Ca2+ release. In contrast, group II and group III receptors are typically located on presynaptic nerve terminals and act as inhibitory autoreceptors. Activation of these receptors causes the inhibition of Ca2+ channels, resulting in inhibition of transmitter release. These receptors are activated only when the concentration of glutamate rises to high levels during repetitive stimulation of the synapse. Activation of these receptors also causes the inhibition of adenylyl cyclase and decreases cAMP generation.
TABLE 21–2 Summary of neurotransmitter pharmacology in the central nervous system.
TABLE 21–2 Summary of neurotransmitter pharmacology in the central nervous system. (Continued)
Note: Many other central transmitters have been identified (see text).
ACET, (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione; ACPD, trans-1-amino-cyclopentyl-1,3-dicarboxylate; AMPA, DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate; LSD, lysergic acid diethylamide; MCPG, α-methyl-4-carboxyphenylglycine; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline.