ReviewAdenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors
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
References (252)
- et al.
Changes in adenosine receptors in the neonatal brain following hypoxic ischemia
Mol. Brain Res.
(1994) - et al.
Phosphorylation of an α1-like subunit of an ω-conotoxin-sensitive brain calcium channel by cAMP-dependent protein kinase A and protein kinase C
J. Biol. Chem.
(1991) - et al.
Facilitation by arachidonic acid of acetylcholine release from the rat hippocampus
Brain Res.
(1999) - et al.
Inhibition of N-, P/Q- and other types of Ca2+ channels in rat hippocampal nerve terminals by adenosine A1 receptor
Eur. J. Pharmacol.
(1997) - et al.
Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship
Brain Res.
(1999) - et al.
Apoptosis by 2-chloro-2′-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells
Neurochem. Int.
(1998) Normal aging: regionally specific changes in hippocampal synaptic transmission
Trends Neurosci
(1994)- et al.
The local regulation of cerebral blood flow
Prog. Cardiovasc.Dis.
(1981) - et al.
Prevention of cycloheximide-induced apoptosis in hepatocytes by adenosine and by caspase inhibitors
Biochem. Pharmacol.
(1999) - et al.
Activation of NO-cGMP signalling pathway depresses hippocampal synaptic transmission through an adenosine receptor-dependent mechanism
Neuropharmacology
(1994)
Purines and their roles in apoptosis
Neuropharmacology
Tonic adenosine A2A receptor activation modulates nicotinic autoreceptor function at the rat neuromuscular junction
Eur. J. Pharmacol.
Adenosine uptake and deamination regulate tonic A2a-receptor facilitation of evoked [3H]-ACh release from the motor nerve terminals
Neuroscience
On slices, synaptosomes and dissociated neurones to study in vitro ageing physiology
Trends Neurosci.
Extracellular metabolism of adenine nucleotides and adenosine in the innervated skeletal muscle of the frog
Eur. J. Pharmacol.
Evidence for functionally important adenosine A2a receptors in the rat hippocampus
Brain Res.
Adenosine A2A receptors stimulate acetylcholine release from nerve terminals of the rat hippocampus
Neurosci. Lett.
Non-selective effects of adenosine A1 receptor ligands on energy metabolism and macromolecular biosynthesis in cultured central neurons
Biochem. Pharmacol.
Endogenous adenosine modulates long-term potentiation in the hippocampus
Neuroscience.
An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus
Neurosci. Lett.
Mechanism of adenosine accumulation in the hippocampal slice during energy deprivation
Neurochem. Int.
Medium- and long-term alterations of brain A1 and A2A adenosine receptor characteristics following repeated seizures in developing rats
Epilepsy Res.
The physiological role of adenosine in the central nervous system
Int. Rev. Neurobiol.
Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia
Trends Neurosci.
Contributions of Na+ flux and the anoxic depolarization to adenosine 5′-triphosphate levels in hypoxic/hypoglycemic rat hippocampal slices
Neuroscience
Hydroxylamine blocks pre- but not post-synaptic adenosine A1 receptor-mediated actions in rat hippocampus
Brain Res.
Interactions of the bovine brain A1-adenosine receptor with recombinant G protein α-subunit Selectivity for rGiα−3
J. Biol. Chem.
Modulation of apoptosis by adenosine in the central nervous system: a possible role for A3 receptor. Pathophysiological significance and therapeutic implications for neurodegenerative disorders
Ann. N. Y. Acad. Sci.
A single species of A1 receptor expressed in chinese hamster ovary cells not only inhibits cAMP accumulation but also stimulates phospholipase C and arachidonate release
Mol. Pharmacol.
Release of neurotransmitter amino acids from rat brain synaptosomes and its regulation in aging
Gerontology
The control of the metabolism and the hormonal role of adenosine
Essays Biochem
The G-protein Go in mammalian cardiac muscle: localization and coupling to A1 adenosine receptors
J. Biochem. (Tokyo)
Inhibition by adenosine receptor agonists of synaptic transmission in rat periaqueductal gray neurons
J. Physiol.
Supply-to-demand ratio for oxygen determines formation of adenosine by the heart
Am. J. Physiol.
Adenosine A1 receptor inhibition of glutamate exocytosis and protein kinase C-mediated decoupling
J. Neurochem
Age-dependence of effects of A1 adenosine receptor antagonism in rat hippocampal slices
J. Neurophysiol.
Probabilistic secretion of quanta from nerve terminals in avian ciliary ganglia modulated by adenosine
J. Physiol.
Evidence for regulated coupling of A1 receptors by phosphorylation in Zucker rats
Am. J. Physiol.
Release of adenosine from ischaemic brain
Circ. Res.
Adenosine A1 receptor agonists as clinically viable agents for treatment of ischemic brain damage
Ann. N. Y. Acad. Sci.
Inhibitory avoidance learning inhibits ectonucleotidases activities in hippocampal synaptosomes of adult rats
Neurochem. Res.
Adenosine-stimulated astroglial swelling in cat cerebral cortex in vivo with total inhibition by a non-diuretic acylaryloxyacid derivative
J. Neurosurg
Upregulation of the enzymes chain hydrolysing extracellular ATP after transient forebrain ischemia in the rat
J. Neurosci.
Modulation of excitatory synaptic transmission by adenosine released from single hippocampal pyramidal neurons
J. Neurosci.
Protein kinase C-mediated supression of the presynaptic adenosine A1 receptor by a facilitatory metabotropic glutamate receptor
J. Neurochem.
Regulation of glutamate and aspartate release from slices of the hippocampal CA1 area: effects of adenosine and baclofen
J. Neurochem.
Morphine activates omega-conotoxin-sensitive Ca2+-channels to release adenosine from spinal cord synaptosomes
J. Neurochem.
Presynaptic enhancement of inhibitory synaptic transmission by protein kinases A and C in the rat hippocampus
J. Neurosci.
Presynaptic inhibition of calcium-dependent and calcium-independent release elicited with ionomycin, gadolinium, and α-latrotoxin in the hippocampus
J. Neurophysiol.
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