This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

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Physiology and Pathophysiology of Purinergic Neurotransmission

2. Evidence for A m i n o Acids as T ransmi t t e r s . . . . . . . . . . . . . . . . . . . . 99 2.1. Synthesis and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.2. Synapt ic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3. Postsynapt ic Act ion . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.4. Postsynapt ic An tagon i s t s . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.5. Inac t iva t ion and R e m o v a l . . . . . . . . . . . . . . . . . . . . . . . . . 104

Amino acid transmitters in the mammalian central nervous system

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

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Cellular distribution and functions of P2 receptor subtypes in different systems.

The role of adenosine and its nucleotides in central synaptic transmission.

Publisher Summary This chapter discusses the physiological role of adenosine in the central nervous system (CNS). In particular, the chapter's attention is directed to the actions of adenosine and related purines in the CNS. One of the major advances in the understanding of purine actions in the central nervous system is the characterization of high affinity specific receptors for purines in brain membranes. The physiological actions of purines, the receptors and biochemical actions that underlie these functional responses and behavioral responses to purinergic drugs are considered. There are three different adenosine receptor sites in brain, which can be distinguished primarily by their effects upon adenylate cyclase, their pharmacological properties, and by their ability to bind labeled analogs of adenosine. One of the best-characterized physiological actions of adenosine is the inhibition of the release of neurotransmitters, an action that has been unequivocally established at many peripheral synapses. If one thing remains clear, it is that purines have a multitude of complex actions at every level, including the biochemical, physiological, and behavioral. There remains little question, but that adenosine or other purines constitute important and rather ubiquitous regulators of neuronalactivity in brain. Despite the evidence that purines play a significant role in neural function, it has remained difficult to define the functional role(s) of purines in brain.

The physiological role of adenosine in the central nervous system.

1. Cuneate cells in anaesthetized cats were strongly excited by L-glutamate, and somewhat less by D-glutamate; cells which receive afferents from hair receptors were particularly sensitive.

2. Glutamate could be used to demonstrate post-synaptic inhibitory inputs from the dorsal column, the medial lemniscus and the frontal cortex.

3. Many cuneate cells were also strongly excited by adenosinetriphosphate (ATP); this was probably due to the chelating action of ATP, as citric acid was also quite effective.

4. γ-Aminobutyric acid (GABA) readily blocked all forms of spontaneous and evoked activity, except antidromic invasion of cuneothalamic neurones; cells which receive proprioceptive afferents were particularly sensitive to GABA. Glycine had a comparable effect.

5. Acetylcholine (ACh), catecholamines, histamine, 5-hydroxytryptamine (5-HT) and an extract containing substance P mostly had only weak depressant actions. Cholinergic and mono-aminergic mechanisms are probably not very significant in the cuneate.

6. These results are consistent with the possibility that glutamate and GABA (or glycine), or some closely related compounds, are the main excitatory and inhibitory transmitters in the cuneate nucleus.

7. If ATP is released from afferent nerve endings, it could also play a significant role in excitation.

Micro‐iontophoretic studies on neurones in the cuneate nucleus

In cats under pentobarbitone anaesthesia, single cuneate cells excited directly by microiontophoresis of glutamate (or ATP) reproduce the temporal patterns of firing seen during spontaneous activity or during activity evoked by peripheral stimulation. In particular, the glutamate-evoked discharges of hair or touch cells show their characteristic tendency to fire in high-frequency pairs or bursts of impulses. Since glutamate acts mainly on the post-synaptic cell, the explanation for the multiple discharges must lie in special, repetitive properties of the hair and touch cells. Cuneate neurones are strongly excited by microiontophoretic applications of Flaxedil. The most prominent effect is the appearance of prolonged bursts of spikes at a high frequency. Even systemic Flaxedil can alter the discharge of cuneate hair cells; short intervals occur more frequently, and, in some cases, there is an acceleration in spontaneous firing.

A. Galindo

Papers

Micro‐iontophoretic studies on neurones in the cuneate nucleus

Patterns of firing in cuneate neurones and some effects of flaxedil