Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity
Section snippets
Adenosine in the brain
Adenosine is a prototypic neuromodulator in the nervous system, which means it does not trigger direct neuronal responses but instead fine tunes on-going synaptic transmission. The impact of adenosine modulation is more evident in the control of excitatory rather than inhibitory synapses (reviewed in Dunwiddie and Masino, 2001). The most widely recognised effects of adenosine are operated through inhibitory A1 receptors, one of the most abundant G protein-coupled receptors in brain tissue (
Effects of endogenous adenosine in brain circuits
Apart from the basal ganglia, the experience of the vast majority of researchers exploring adenosine modulation is that adenosine essentially fulfils an inhibitory role mediated by inhibitory A1 receptors (reviewed in Dunwiddie and Masino, 2001). In particular, the seminal work of Tom Dunwiddie has revealed that there is an inhibitory tonus mediated by endogenous adenosine that results from the activation of A1 receptors (Dunwiddie, 1980). This agrees with the general findings that the addition
Source of endogenous extracellular adenosine
The source of endogenous extracellular adenosine during physiological conditions of neuronal firing has been one of the less studied aspects of adenosine neuromodulation. There are two potential metabolic sources able to generate extracellular adenosine: (1) release as such, or (2) extracellular formation from released adenosine nucleotides.
The formation of adenosine from released adenine nucleotides is based on the observation that most cell types in the brain can release ATP (reviewed in
Adenosine as a hetero-synaptic modulator—A1 receptors
Several groups noted that the blockade of ecto-nucleotidases decreases the extracellular levels of endogenous adenosine in brain slices (Pascual et al., 2005, Martin et al., 2007, Serrano et al., 2006). In particular, the innovative methodology devised by Nicholas Dale to quantify on-line the extracellular levels of ATP and adenosine (Llaudet et al., 2005, Pearson et al., 2001) confirmed that the extracellular catabolism of ATP contributed for the basal extracellular levels of adenosine in
Adenosine as a synaptic modulator—A2A receptors
This ‘paracrine’-like role of adenosine acting broadly in large groups of synapses in a non-synaptic (Vizi, 1984) or volume transmission-like manner (Agnati et al., 1986) should not underscore a complementary role fulfilled by adenosine as an ‘autocrine’-like signalling molecule restricted to a particular synapse. In fact, there is ground to propose that the role of adenosine in the control of synaptic plasticity might not only be limited to the ‘paracrine’-like action of inhibitory A1
An integrated view of adenosine modulation
Overall, the ‘paracrine’-like role of A1 receptor-mediated inhibition and the ‘autocrine’-like facilitatory role of A2A receptors work in tandem to guarantee a maximal salience between stimulated and non-tetanised synapses (Fig. 1). At low frequencies of nerve stimulation (used in the majority of studies), it is only possible to highlight a role of A1 receptors, which impose a global tonic inhibition of excitatory transmission designed to decrease noise (Fig. 1, upper panel). Facilitatory A2A
Acknowledgments
Due to space limitations, I mostly quoted reviews rather original papers, thus leaving unquoted several colleagues, to whom I apologise. I thank the continuous support of Fundação para a Ciência e a Tecnologia and the continuous discussions with the lab members and different colleagues over the years.
References (79)
- et al.
Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices
Neuroscience
(2003) Adenosine kinase, epilepsy and stroke: mechanisms and therapies
Trends Pharmacol. Sci.
(2006)- et al.
Storage and release of ATP from astrocytes in culture
J. Biol. Chem.
(2003) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors
Neurochem. Int.
(2001)- et al.
Modification by arachidonic acid of extracellular adenosine metabolism and neuromodulatory action in the rat hippocampus
J. Biol. Chem.
(2000) - et al.
Inactivation of adenosine A2A receptors impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission
Neuroscience
(2001) - et al.
Neuronal activity triggers calcium waves in hippocampal astrocyte networks
Neuron
(1992) - et al.
Adenosine: does it have a neuroprotective role after all?
Brain Res. Rev.
(2000) - et al.
Omega-conotoxin differentially blocks acetylcholine and adenosine triphosphate releases from Torpedo synaptosomes
Neuroscience
(1992) - et al.
Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors
Neuron
(2004)