Regarding A Rs and A ARs basal conditions generate a

Regarding A1Rs and A2ARs, basal conditions generate a low tone of endogenous adenosine and cause A1R activation, in contrast to situations of increased adenosine where A2AR activation becomes dominant. When adenosine concentrations rise, e.g. during hypoxia, also time appears likely important in regulating A2AR activity. That means A2ARs are “active” under prolonged stimulation [45]. Finally, activation of the A1R/A2AR heteromer contributes to A2AR signaling when adenosine level is elevated, and may provide a mechanism to facilitate plastic changes in the excitatory synapse [23]. Consequently, the results of the above mentioned studies support the notion that A1Rs and A2AR regulate the synaptic transmission synergistically via forming A1R–A2AR heteromers.
The A3R was the latest receptor subtype of the adenosine receptor family to be identified, and its functional role is still controversially discussed [32]. A dual, biphasic role in neuroprotection has been described depending on experimental approach, both in vitro and in vivo [65,66,72,76,81–84]. A3Rs couple to inhibition of adenylyl cyclase as well as to activation of PLC, and to elevation of inositol triphosphate levels [2,68]. Furthermore, an increase in intracellular Ca2+ levels due to release from intracellular stores and Ca2+ influx has been described [35,44]. One interesting example of A3Rs functional role is their involvement in acute neurotoxic situations and interplay with A1Rs. A potential of A3Rs to modify responses via A1Rs in the hippocampus has been postulated [20]. In vitro experiments on rat calcium sensing receptor slices approved that the activation of hippocampal A3Rs induced a desensitization of A1Rs. This phenomenon was thought to reduce the protective effects of endogenous adenosine caused by the lack of sensitivity of A1Rs. Further investigations on pyramidal cells of the rat cingulate cortex did not confirm these results [9]. In this brain area, A1Rs and A3Rs did not show any interaction. The receptor subtypes were unable to affect each other. The discrepancy was taken to be a genetic phenomenon, such as alternative splicing of the rat A3R transcript causing distinguished pharmacological and functional properties in the brain. Furthermore, Hentschel et al. [39] demonstrated the involvement of A3Rs in inhibition of excitatory neurotransmission during hypoxic conditions, indicating a neuroprotective action of endogenously released adenosine on A3Rs in addition to A1Rs. Lastly, Lopes et al. [48] attempted to define the possible role of A3Rs in the rat hippocampus using experiments in non-stressful and stressful situations, with particular attention to whether A3Rs control A1Rs. These data suggested that no interaction between the two receptor subtypes exist, but confirm that A3Rs do not affect synaptic transmission on superfusion with an A3R agonist or an A3R antagonist. The authors pointed out that the agonist binds to A1Rs even at low nanomolar concentrations and to the A3Rs in higher concentration. Heterodimerization between both receptor subtypes was not described so far [51]. It seems that these receptors subtypes act additively or were activated at different concentration of extracellular adenosine. Another explanation is that the A3Rs are active after desensitization of the A1Rs. This could be a functional synergistic effect. Thus, the existence of a possible interaction between A1Rs and A3Rs has to wait for reliable ligands.
Interaction between adenosine receptors and dopamine receptors Dopamine is an important transmitter in the striatum, and is noted for influencing motor activity, playing an important role in Parkinson's disease. In vivo and in vitro data on adenosine-dopamine interactions were mostly obtained from investigations in the basal ganglia and limbic regions [27,57] due to the high abundance of A1Rs, A2ARs, dopamine D1 receptors (D1Rs) and dopamine D2 receptors (D2Rs) in these areas and their involvement in the pathology of Parkinson's disease. Sufficient endogenous adenosine is present interstitially in the substantia nigra pars reticulata to control dopaminergic effects. The effects of adenosine are absent when dopaminergic influence is suppressed [27]. There also is an anatomical basis for the existence of functional interactions between A1Rs and D1Rs in the same neurons. Moreover, recently it has been shown in caudate-putamen slices that adenosine modulates dopamine release also via A1R [71].