Excitatory Amino Acids: Ten Years Later.
This book comprises 30 reports from participants in the second meeting on excitatory amino acids (EAAs), held in Manaus, Brazil in 1998, and the somewhat puzzling subtitle "Ten Years Later" refers to the decade between this and the first meeting, also held in Manaus. During this period, many of the EAA receptor genes were cloned, and the field began to take on a more defined shape. Although this book reflects some of those advances, the study of EAAs has become one of the largest and most active areas in contemporary neuroscience; the field is now so large that a small meeting such as this one could not be expected to encompass it all.
The amino acid glutamate is regarded as the major EAA; others, such as aspartate, have received much less attention. Glutamate is the principal fast-acting neurotransmitter in the mammalian central nervous system (CNS), where it mediates signaling at 75-90% of synapses. This signaling involves six major functional classes of receptors: three classes of ligand-gated ion channels (ionotropic receptors) and three classes of G-protein-coupled receptors (metabotropic receptors). Each functional class includes multiple gene families, and of course, some of the mRNAs undergo alternative splicing. The end result is a large number of receptor proteins (>23 at present). One or more of these receptors are expressed by virtually every neuron in the CNS.
The simple classification of receptors as ionotropic or metabotropic also is beginning to blur as reports accumulate that, for example, activation of ionotropic kainate receptors may also produce a second-messenger cascade. Sorting out the functional and pharmacologic implications of multiple receptors in multiple brain circuits is bound to keep people entertained for years. In addition, some EAA receptors can mediate excitotoxic cell death and are thought to contribute to CNS damage in stroke, ischemia, and other pathologies. Thus, the EAAs have been the focus of a great deal of pharmacologic research.
The book is concerned mainly with receptor pharmacology and receptor-mediated processes. Thirteen chapters deal with N-methyl-n-aspartate (NMDA) receptors, 8 with 2-amino-3-hydroxy-5-methyl-4-isoxazole propicnic acid (AMPA) receptors, 6 with kainate receptors, and 6 with metabotropic receptors. There are two interesting short chapters on receptor localization by immunogold labeling and electron microscopy, but nothing on the structure or molecular analysis of the receptors. There are no chapters focused on other important aspects of function, such as EAA metabolism, compartmentation, storage, or transport.
Several chapters, mainly from pharmaceutical companies, reflect the continuing interest in developing EAA antagonists to treat the various pathologies in which EAAs are thought to be important. The topics include studies of noncompetitive NMDA receptor antagonists, systemically active antagonists at the NMDA glycine site, AMPA and NMDA antagonists that are active in vivo, antagonists of group I metabotropic glutamate receptors, and AMPA antagonists for therapy of stroke and trauma. Such chapters may be most useful to those who are looking for experimentally interesting compounds for their studies.
The chapters on EAA function cover a wide range of topics. Some, such as epilepsy or long-term potentiation in the hippocampus, are the subjects of entire meetings. These chapters, although interesting, are mere samples of an enormously larger literature. Other topics, such as the utility of EAA pharmacology in schizophrenia, depression, stress/anxiety behaviors, and animal models of psychosis, are much less developed and represent future opportunities.
Like most meeting summaries, this book is directed at the specialist, and there is no attempt to lay any groundwork for newcomers to the field. I found some chapters interesting because they introduced me to new material or because they were useful short reviews. There is an author index, but no subject index.
David L. Martin
New York State Department of Health
Albany, NY 12201-0509