Evidence for the Existence of a Specific G Protein‐Coupled Receptor Activated by Guanosine

Abstract

Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a G protein-coupled receptor that is different from the well-characterized adenosine receptors.

Guanosine and its role in neuropathologies

“…Indeed, a G-protein-coupled site seems to be important for the neuroprotective effects of this nucleoside, namely, during the guanosine-induced stimulation of glutamate uptake and the release of trophic factors by astrocytes [39,82,86]. In support of this hypothesis, binding sites for guanosine, distinct from the well-characterized P1 and P2 receptors, were found in rat brain membranes [87][88][89]. In addition, experimental evidence suggests that this binding site has an important role in signal transduction mediated by this nucleoside [39,82,86].…”

Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation

“…GUO prevents the decrease in cell viability, by increasing glutamate uptake and glutamine synthetase activity, decreasing glutamate release, ROS production and inflammatory mediators expression, including reduction of iNOS expression [14,15,33,40]. The exact interaction site of GUO in cellular membranes is still unknown, although it has been suggested [41,42]. GUO effects over adenosinergic system are controversial [43], but we have shown that neuroprotective effects of GUO depend on adenosine receptors modulation [33] and on activation of a calcium-dependent potassium channel [14].…”

The Antiepileptic Potential of Nucleosides

“…1 and Table 1). In addition, a great deal of evidence suggests that both Urd [83,84] and Guo [50,51] may bind to their selective receptors, most likely the G-proteincoupled receptors UrdR and GuoR, in the CNS (Fig. 1). …”

“…Guo may bind to its putative (uncloned) G-protein-coupled receptors in the brain [50,51]. Guanosine levels increased after PTZ-induced seizures [372], and Guo exerts a protective effect on quinolinic acid (QA)-induced seizures [60-62, 368, 373-377] (Table 4) and -dendrotoxin-induced seizures [371] likely by stimulation of astrocytic glutamate uptake [89,373,377,378].…”

“…There is considerable evidence for neuromodulatory functions of nucleosides. Adenosine and Guo can be released from synaptosomes [44][45][46][47][48][49] and may then bind to their specific receptors [32,50,51]; thus, Ado, Guo and most likely Urd [52] may be signaling molecules (neuromodulators or neurotransmitters) in the brain. Area-, age-and genderdependence of nucleoside levels and/or nucleoside metabolism, nucleoside transporters and nucleoside receptors in the brain have been described previously, suggesting that nucleosides have different physiological and pathophysiological Fig.…”