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Research within the past decade has provided compelling evidence that anaesthetics can act directly as allosteric modulators of transmitter-gated ion channels. Recent comparative studies of the effects of general anaesthetics across a structurally homologous family of inhibitory amino acid receptors that includes mammalian GABAA, glycine and Drosophila RDL GABA receptors have provided new insights into the structural basis of anaesthetic action at transmitter-gated channels. In this article, the differential effects of general anaesthetics across inhibitory amino acid receptors and the potential relevance of such actions to general anaesthesia will be discussed.

Excitatory amino acid transmitters participate in normal synaptic transmission throughout the CNS (see Headley and Grillner, May TiPS ), so it comes as no surprise that such excitatory pathways are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, although more recent evidence indicates potential roles for the AMPA receptors as well. In this article — the first of two to focus on the neurological dangers inherent in excitatory amino acid pathways — Raymond Dingledine, Chris McBain and James McNamara consider their involvement in epilepsy; next month's article will cover brain damage following ischemia and hypoxia.

As we have learnt from earlier articles in our series on the pharmacology of excitatory amino acids, neurons and glia express several subtypes of excitatory amino acid receptor, the activation of which increases intracellular free calcium ion concentration. In this sixth article, Mark Mayer and Richard Miller detail the mechanisms and consequences of this activity. Ionotropic excitatory amino acid receptors, most notably those activated by NMDA, allow Ca2+ influx as a result of passive diffusion down its concentration gradient. Metabotropic receptors trigger an increase in polyphosphoinositide metabolism, and release of Ca2+ from intracellular stores. The increase in [Ca2+]i mediated by excitatory amino acids underlies a complex cellular physiology, including the activation of other second messenger systems, and contributes to the initiation of long-term potentiation.

Ion channels coupled to NMDA, kainate and AMPA receptors are the target of pharmacological regulation by a variety of drugs and ions. While these channels are all nonselectively permeated by Na+ and K+ ions, the NMDA receptor-channel complex contains a number of pharmacological sites distinct from those found on the others. For example, Mg2+ ions rapidly and reversibly block open NMDA channels in a highly voltage-dependent manner. Its extreme voltage dependence suggests that the Mg2+ binding site lies deep within the ion channel pore. By contrast the voltage-dependent block of activated channels by the dissociative anesthetic 'slow channel blockers' has unusual characteristics. In the fourth article in our series on excitatory amino acids, John MacDonald and Linda Nowak analyse the characteristics of these two types of block and describe the hypotheses that have been put forward to explain the mechanisms involved.

In last month's article in this series, Lodge and Johnson discussed the contribution of noncompetitive excitatory amino acid antagonists to understanding of these receptors. In this third article Anne Young and Graham Fagg describe how radioligand binding experiments have helped to fuel the recent burst of progress in understanding excitatory amino acid receptors in the brain. New and selective radioligands have facilitated mapping the distributions of the major excitatory receptor subtypes in normal and diseased brain, examining allosteric interactions within the NMDA receptor, searching for novel therapeutic agents and determining drug mechanisms, and making first steps along the path to defining receptor structure at the molecular level.

Metabotropic glutamate receptors (mGluRs) are a novel family of recently cloned G protein-coupled receptors. These receptors are heterogeneous and coupled to multiple second messenger systems that include increases in phosphoinositide hydrolysis, activation of phospholipase D, decreases in cAMP formation, increases in cAMP formation, and changes in ion channel function. Using the selective mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid (1s,3R-ACPD), considerable progress has been made towards understanding the role of this glutamate receptor class in the central nervous system. This article reviews the molecular aspects and pharmacology of mGluRs, and recent studies elucidating their role in brain function and pathology.

In this article in the TiPS series on the pharmacology of excitatory amino acids Eric Barnard and Jeremy Henley report on the very recent advances in protein purification and molecular biology of their receptors. Although the NMDA receptor, which is the best characterized of these pharmacologically, has not yet yielded to recombinant DNA technology, several different clones encoding subunits of non-NMDA excitatory amino acid receptors have been reported. From the properties of these and of a purified non-NMDA receptor, and the pharmacology of the native responses to AMPA and kainate, the authors conclude that multiple non-NMDA subtypes exist and that one of these is a unitary receptor that can respond to both kainate and AMPA.

Excitatory amino acid receptors are the mediators of synaptic transmission at many synapses that can undergo use-dependent modifications of synaptic efficiency. They also play an essential role in the induction of these plastic changes. Graham Collingridge and Wolf Singer describe how NMDA receptors can endow synapses with hebbian-like properties and discuss how these may be used by vertebrates for associative learning and experience-dependent modifications of synaptic connections during development. The role of AMPA receptors in the maintenance of long-term potentiation is also discussed.

In the first article in this series, Watkins, Krogsgaard-Larsen and Honore outlined the structure-activity requirements at the receptor sites for excitatory amino acids in the mammalian CNS. The postsynaptic depolarizing actions of glutamate are thought to be mediated by NMDA, AMPA and kainate receptors. Here David Lodge and Kenneth M. Johnson review some of the recent developments in the pharmacology of other means by which the function of these receptors may be modulated. Divalent cations, phencyclidine-like drugs, glycine analogues and polyamines all modulate NMDA receptors whereas barbiturates and some arthropod toxins reduce channel responses to non-NMDA receptor agonists. Modes of action and implications for physiology and pathophysiology are discussed.

Development of new selective ligands for excitatory amino acid receptors has been fundamental in supporting this rapidly developing field. Some of the most important ligands have come from the laboratories of Jeff Watkins, Povl Krogsgaard-Larsen and Tage Honore, who collaborate in this double-length review to describe the chemical features and SARs of agonists and antagonists, particularly those features associated with subtype selectivity.