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    • Extracellular adenosine acts as a

    2023-09-18

    Extracellular adenosine acts as a local modulator of cell function via four adenosine receptor subtypes (A1Rs A2AR, A2BR, and A3R) that are involved in numerous physiological and pathophysiological processes [31]. Each is encoded by a separate gene and has different functions, although with some overlap [34]. Evidence for the existence of G protein-coupled receptor homomerization and heteromerization is growing continuously. There are numerous reviews about central nervous system that describe regulation of kx2 adenosine levels, adenosine receptors, their cellular and subcellular localization, signaling pathways and function in the brain under physiological and pathophysiological conditions as well as selective receptor agonists and antagonists [1,30,42,59,78]. Additionally, a set of publications has demonstrated the existence of potential adenosine receptor interactions. In this context, the excellent review of Ciurela and co-workers summarized the recent significant developments based on adenosine receptor interactions that are essential for acquiring a better understanding of neurotransmission in the central nervous system [11]. Either through direct receptor–receptor modulation or beyond the receptor pathways, adenosine might synchronize or desynchronize synaptic transmission in order to fine-tune the nervous system. This opens novel possibilities for the action of this nucleoside [10]. Using adenosine receptors as paradigm of GPCRs, this review focuses on how receptor–receptor interactions contribute synergistically or antagonistically to processes within the central nervous system. Considering the various types of receptors, one may expect to find three principle paths of receptor interaction: (i) interactions between metabotropic receptors (ii) interactions between a metabotropic receptor and an ionotropic receptor and (iii) interactions between ionotropic receptors. The examples mentioned below stem from the first and second type of interaction. Synergistic, additive and antagonistic effect will be discussed.
    The A1Rs are the best characterized of the widely distributed purinergic receptor family. This might result from a highly localized distribution of A1Rs in the active zone and postsynaptic density of CNS synapses, especially in hippocampus [50] and prefrontal cortex [63]. A1Rs can be clearly distinguished from A2Rs on the basis of structure activity relationships with selective ligands. A2ARs are widely distributed in the CNS, but local and subcellular differences in allocation exist. The A2ARs occur predominantly on neurons in the striatum, especially the GABAergic projection neurons and on cholinergic interneurons [62]. A2ARs are also found in lower density in neurons in the neocortex and limbic cortex [30]. There is abundant evidence from biochemical and electrophysiological investigations that the activation of A2ARs promotes the release of neurotransmitters [16] Co-localization of A1Rs and A2ARs was approved for glutamatergic nerve terminals in the hippocampus [70]. In the striatum, A1R–A2AR heteromers were found on synapses of medium spiny neurons and integrated in the presynaptic membrane of glutamatergic terminals that represent the cortical–limbic-thalamic input [22]. A1R and A2ARs may closely interact in such a way that activation of A2AR receptors can lead to inhibition of A1R-mediated responses [49]. However, problems arise due to long-term desensitization of A1Rs. Evidence should be that A2ARs do not up-regulate after antagonist administration, but have a low abundance in hippocampal and cortical areas compared with A1Rs [17,64,87]. A1Rs and A2ARs cannot be regarded in isolation from one another since cross talk between the subtypes has been described several times [12,13,19,48,67]. A2AR activation by agonists caused A1R desensitization resulting in decreased binding affinity for agonists in the hippocampus of young rats. Controlling A1Rs by A2ARs was mediated by protein kinase C in a cAMP-independent manner. A2AR activation was seen to play a role in fine-tuning A1Rs by attenuating the tonic effect of presynaptic A1Rs located on glutamatergic nerve terminals [12,13,19,48,49]. One implication of this interaction is that, when the extracellular level of adenosine reaches levels sufficient to activate A2ARs, as it can do after hypoxia, it may inhibit A1Rs function [28]. Some results support this assumption. It has recently been demonstrated that A2ARs receptors localized in striatal glutamatergic terminals play a very important role in control of striatal glutamate release [12,13]. These receptors form heteromers with A1Rs, and the A1R–A2AR heteromer constitutes a “concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. As in the hippocampus, A2AR stimulation decreased the affinity of A1Rs for agonists. The A1R–A2AR heteromer allows adenosine to perform a detailed modulation of glutamate release [12,13,67]. Finally, Cristovao-Ferreira et al. [14] showed in primary cultures of rat astrocytes that a further level of regulation of GABA uptake occurs through A1R–A2AR heteromers.