While adenine-based purines (ABPs), including adenosine triphosphate, diphosphate, and monophosphate (ATP, ADP, and AMP, respectively), and adenosine (ADO), have been extensively studied as extracellular signalling molecules in the central nervous system (CNS) ( Burnstock, 2018 Jacobson et al., 2020 Illes et al., 2021), the guanine-based purines (GBPs), comprising guanosine triphosphate and monophosphate (GTP and GMP, respectively), guanosine (GUO), and guanine (GUA) has attracted less interest, although they also display CNS effects.
Overall, these data suggest GPR23 involvement in modulating responses to GUA in tumor cell lines, although further research needs to verify whether this receptor mediates other GUA effects.
Finally, binding experiments using -GUA and U87 cell membranes revealed the existence of a selective GUA binding (K D = 29.44 ± 4.07 nM Bmax 1.007 ± 0.035 pmol/mg prot) likely to GPR23. Furthermore, while GPR23 expression was low in a hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)-mutated melanoma cell line showing poor sensitivity to GBPs, and in HGPRT-silenced glioma cells, GPR23-induced expression in both cell types rescued GUA-mediated cell growth inhibition.
Accordingly, cells stably expressing GPR23 showed increased sensitivity to GUA. Guanine (GUA) was the most potent compound behind the GPR23-mediated effect, acting as the endpoint effector of GBP antiproliferative effects. Of the GPRs chosen, only the silencing of GPR23, also known as lysophosphatidic acid (LPA) 4 receptor, counteracted GBP-induced growth inhibition in U87 cells. To shed light on this question, we screened orphan and poorly characterized G protein-coupled receptors (GPRs), selecting those that showed a high purinoreceptor similarity and were expressed in glioma cells, where GBPs exerted a powerful antiproliferative effect. Guanine-based purines (GBPs) exert numerous biological effects at the central nervous system through putative membrane receptors, the existence of which is still elusive.
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