l-Glutamate is the primary excitatory neurotransmitter in the vertebrate central nervous system (CNS) (1-5). This conclusion, based on innumerable pharmacological, physiological, and biochemical studies, is now succinctly confirmed by the characterization of the vesicular glutamate transporters and their localization throughout the brain (6). In contrast to the neuromodulatory neurotransmitters that are commonly released by brainstem nuclei projecting diffusely to large regions of the brain, and in contrast to the inhibitory, nonprojecting, local circuit neurons that use γ-aminobutyric acid (GABA) or glycine, glutamate-using pathways provide fast signaling between discrete brain regions. (For further discussion of glutamate-using pathways, see Chapter 3). l-Glutamate released from presynaptic nerve terminals binds to glutamate receptors on the receiving neuron. The ionotropic glutamate receptors span the plasma membrane and the binding of l-Glutamate causes a conformational change that opens a pore in the membrane formed by the receptor complex. The opened ion channel allows the influx of Na+, and sometimes Ca++ ions, causing the cell to depolarize. If sufficiently depolarized, the neuron is activated. It is the fast-acting ionotropic glutamate receptors that underlie fast electrical responses in the CNS. Unexpectedly, there is also a wealth of slower-acting G protein-coupled glutamate receptors, the metabotropic glutamate receptors. The metabotropic receptors are the subject of Chapter 5 in this volume. The discovery and characterization of l-glutamate as the major CNS neurotransmitter was a major breakthrough and has opened the door to understanding many essential aspects of brain function at all levels of investigation.
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