Using the criteria above, a vast number of small molecules have been isolated from the brain, and studies using a variety of approaches suggest that the agents listed in Table 21–2 are neurotransmitters. A brief summary of some of these compounds follows.
The amino acids of primary interest to the pharmacologist fall into two categories: the acidic amino acid glutamate and the neutral amino acids glycine and GABA. These compounds are present in high concentrations in the CNS and are extremely potent modifiers of neuronal excitability.
A. Glutamate
Excitatory synaptic transmission is mediated by glutamate, which is present in very high concentrations in excitatory synaptic vesicles (~100 mM). Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis. The released glutamate acts on postsynaptic glutamate receptors and is cleared by glutamate transporters present on surrounding glia (Figure 21–7). In glia, glutamate is converted to glutamine by glutamine synthetase, released from the glia, taken up by the nerve terminal, and converted back to glutamate by the enzyme glutaminase. The high concentration of glutamate in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT).
Almost all neurons that have been tested are strongly excited by glutamate. This excitation is caused by the activation of both ionotropic and metabotropic receptors, which have been extensively characterized by molecular cloning. The ionotropic receptors are divided into three subtypes based on the action of selective agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid (KA), and N-methyl-d-aspartate (NMDA). All the ionotropic receptors are composed of four subunits. AMPA receptors, which are present on all neurons, are heterotetramers assembled from four subunits (GluA1–GluA4). The majority of AMPA receptors contain the GluA2 subunit and are permeable to Na+ and K+, but not to Ca2+. Some AMPA receptors, typically present on inhibitory interneurons, lack the GluA2 subunit and are also permeable to Ca2+.
Kainate receptors are not as uniformly distributed as AMPA receptors, being expressed at high levels in the hippocampus, cerebellum, and spinal cord. They are formed from a number of subunit combinations (GluK1–GluK5). Although GluK4 and GluK5 are unable to form channels on their own, their presence in the receptor changes the receptor’s affinity and kinetics. Similar to AMPA receptors, kainate receptors are permeable to Na+ and K+ and in some subunit combinations can also be permeable to Ca2+. Domoic acid, a toxin produced by algae and concentrated in shellfish, is a potent agonist at kainate and AMPA receptors. Consumption of contaminated shellfish has been implicated in illness in animals and humans.