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Open AccessArticle

Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

1
Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Brazil
2
Programa de Pós-graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Brazil
3
Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, 08907 L’Hospitalet de Llobregat, Spain
4
Institut de Neurociències, Universitat de Barcelona, 08035 Barcelona, Spain
5
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
6
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Brazil
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(12), 1630; https://doi.org/10.3390/cells8121630
Received: 6 November 2019 / Revised: 4 December 2019 / Accepted: 11 December 2019 / Published: 13 December 2019
(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)
Guanosine, a guanine-based purine nucleoside, has been described as a neuromodulator that exerts neuroprotective effects in animal and cellular ischemia models. However, guanosine’s exact mechanism of action and molecular targets have not yet been identified. Here, we aimed to elucidate a role of adenosine receptors (ARs) in mediating guanosine effects. We investigated the neuroprotective effects of guanosine in hippocampal slices from A2AR-deficient mice (A2AR−/−) subjected to oxygen/glucose deprivation (OGD). Next, we assessed guanosine binding at ARs taking advantage of a fluorescent-selective A2AR antagonist (MRS7396) which could engage in a bioluminescence resonance energy transfer (BRET) process with NanoLuc-tagged A2AR. Next, we evaluated functional AR activation by determining cAMP and calcium accumulation. Finally, we assessed the impact of A1R and A2AR co-expression in guanosine-mediated impedance responses in living cells. Guanosine prevented the reduction of cellular viability and increased reactive oxygen species generation induced by OGD in hippocampal slices from wild-type, but not from A2AR−/− mice. Notably, while guanosine was not able to modify MRS7396 binding to A2AR-expressing cells, a partial blockade was observed in cells co-expressing A1R and A2AR. The relevance of the A1R and A2AR interaction in guanosine effects was further substantiated by means of functional assays (i.e., cAMP and calcium determinations), since guanosine only blocked A2AR agonist-mediated effects in doubly expressing A1R and A2AR cells. Interestingly, while guanosine did not affect A1R/A2AR heteromer formation, it reduced A2AR agonist-mediated cell impedance responses. Our results indicate that guanosine-induced effects may require both A1R and A2AR co-expression, thus identifying a molecular substrate that may allow fine tuning of guanosine-mediated responses. View Full-Text
Keywords: guanosine; neuroprotection; oxygen/glucose deprivation; NanoBRET; A1R/A2AR heteromer guanosine; neuroprotection; oxygen/glucose deprivation; NanoBRET; A1R/A2AR heteromer
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MDPI and ACS Style

Lanznaster, D.; Massari, C.M.; Marková, V.; Šimková, T.; Duroux, R.; Jacobson, K.A.; Fernández-Dueñas, V.; Tasca, C.I.; Ciruela, F. Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects. Cells 2019, 8, 1630.

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