Review
Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors

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Abstract

Adenosine exerts two parallel modulatory roles in the CNS, acting as a homeostatic modulator and also as a neuromodulator at the synaptic level. We will present evidence to suggest that these two different modulatory roles are fulfilled by extracellular adenosine originated from different metabolic sources, and involve receptors with different sub-cellular localisation. It is widely accepted that adenosine is an inhibitory modulator in the CNS, a notion that stems from the preponderant role of inhibitory adenosine A1 receptors in defining the homeostatic modulatory role of adenosine. However, we will review recent data that suggests that the synaptically localised neuromodulatory role of adenosine depend on a balanced activation of inhibitory A1 receptors and mostly facilitatory A2A receptors. This balanced activation of A1 and A2A adenosine receptors depends not only on the transient levels of extracellular adenosine, but also on the direct interaction between A1 and A2A receptors, which control each other’s action.

Introduction

Adenosine is a constitutive metabolite of all cells, involved in key pathways such as purinergic nucleic acid base synthesis, amino acid metabolism and modulation of cellular metabolic status (Stone, 1985). Considering this homeostatic role of adenosine related to the control of cellular metabolism (Mcllwain, 1979), adenosine has been termed as ‘local hormone’ (Arch and Newsholme, 1978) and ‘retaliatory metabolite’ (Newby, 1984) to summarise its role in stressful conditions where energy charge is compromised. In such situations, the intracellular concentration of adenosine, which is estimated to be in the nanomolar range, raises to micromolar concentrations (Nordström et al., 1977, Bardenheur and Schrader, 1986) and adenosine is released to the extracellular medium (Meghji, 1991) to refrain cell metabolism of neighbouring cells.

The first suggestion that adenosine might affect neuronal function was advanced 70 years ago (Drury and Szent-Györgyi, 1929). But it was the work of Sattin and Rall (1970) on the effects of adenosine on the accumulation of cAMP in cortical slices together with the observations that adenosine is released from stimulated neuronal preparations (Pull and Mcllwain, 1972) and that exogenously added adenosine modulates neuromuscular transmission (Ginsborg and Hirst, 1972, Ribeiro and Walker, 1973) and cortical neuronal firing (Phillis et al., 1974), that triggered the research on the neuromodulatory effects of adenosine. Although often considered together, the neuromodulatory role of adenosine and its homeostatic role are different. The neuromodulatory role of adenosine may be part of the homeostatic/neuroprotective strategy orchestrated by adenosine, but it may have of limited usefulness for neuroprotection in the CNS once anoxic depolarisation has occurred. Conversely, the powerful homeostatic role of adenosine may have a confoundingly overwhelming effect, when trying to evaluate adenosine neuromodulation, although adenosine neuromodulation occurs in the absence of metabolic imbalance (e.g. Mitchell et al., 1993).

This review will present some hypotheses mainly related to the dual role of adenosine in the nervous system, where it acts as homeostatic modulator, a function common to all cell types, and also as a neuromodulator at the synaptic level, independent of energy metabolism imbalance. In contrast with the inhibitory homeostatic role of adenosine, it is proposed that the neuromodulatory role of adenosine depends on a balance between activation of inhibitory A1 and mainly facilitatory A2A receptors. It will be stressed that there are different ways of generating extracellular adenosine, and that the relative importance of A1 or A2A receptor activation, at the synaptic level, depends on the kinetic properties of the ecto-nucleotidase pathway that generates adenosine from released ATP. Finally, the plasticity of the A1 and A2A receptor set-up will be emphasised based on short-term desensitisation and cross talk between adenosine receptors and on long-term adaptation of adenosine receptors and extracellular metabolism. Although this review contains a number of provocative elements, it is hoped that some of the novel views, once experimentally tested, may provide new insights into the mechanisms of action of adenosine in the nervous system.

Section snippets

Homeostatic modulatory role of adenosine

The main role of adenosine that is observed in different mammalian cell types is the ability of adenosine to refrain cell metabolism (Mcllwain, 1979, Kulinski et al., 1987, Daval and Nicolas, 1998, Zhong et al., 1998). Most often, this adenosine-mediated inhibition of cell metabolism is mimicked by A1 receptor agonists. This leads to the idea that adenosine-induced inhibition of cell metabolism requires A1 receptor activation.

Neuromodulatory role of adenosine

Beside its role as a homeostatic modulator, adenosine also fulfils a neuromodulatory role restricted to the nervous system (Fig. 1), whereby adenosine modulates the release of neurotransmitters, the post-synaptic responsiveness and the action of other receptor systems. Probably the first demonstration of this neuromodulatory role of adenosine occurring independently of the homeostatic role of adenosine was provided by Dunwiddie’s group (Mitchell et al., 1993), who showed the ability of

Differential activation of A1 and A2A receptors in nerve terminals

The coexistence of two types of receptors for adenosine with opposite roles raises the question: what are the control mechanisms to activate inhibitory A1 and facilitatory A2A receptors according to the needs of the system? In some preparations, the role of endogenous extracellular adenosine with respect to A1 and A2A receptor activation has been investigated. It was concluded that, at low concentrations of extracellular adenosine, A1 receptor-mediated inhibition of neurotransmitter release

Short-term plasticity of adenosine neuromodulation — cross talk and desensitisation

The results so far discussed present a view of adenosine neuromodulation in which the output of the ecto-nucleotidase pathway triggers the activation of two different receptors, A1 and A2A, with opposite effects on neurotransmitter release. But, in spite of the ability of the ecto-nucleotidase pathway to deliver appropriate amounts of adenosine to preferentially activate A1 or A2A receptors, the resulting action of adenosine will always be a balanced activation of A1 and A2A receptors. The

Long-term plasticity of adenosine neuromodulation — ageing as an example

If the hypothesis that the ecto-nucleotidase pathway is the main source of adenosine involved in neuromodulation, it is expected that changes in ecto-nucleotidase activity might have parallel occurrence with changes in A1/A2 receptor balance either in physiological or pathological changes in neuronal systems. Our group, at Professor Ribeiro’s lab, has recently launched a project on the changes in extracellular adenosine metabolism and neuromodulation in the hippocampus of aged rats, and the

Concluding remarks

It is hoped that the hypotheses presented in this review may help to resolve some controversies in the literature related to the source of extracellular adenosine, which is likely to be different according to the role of adenosine. It is also hoped that the acceptance of this idea will force a critical evaluation of reports on the relative importance of adenosine receptors for modulation of neurotransmitter where the metabolic status of the preparations was not evaluated. Strong emphasis is

Acknowledgements

This work is a tribute to Prof. J.A. Ribeiro with whom I learned and grew in the adenosine field. The topics more prone to criticism probably reflect the continuous incentive of Prof. Ribeiro for his co-workers to foster plural and divergent opinions that may result in new models. Within his group, discussion is exciting and fruitful, thanks to the good spirit, and scientific excellence of Ana M. Sebastião and Alexandre de Mendonça, as well as to the need to provide convincing explanations to

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