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Purinergic Pharmacology

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Front. Pharmacol. | doi: 10.3389/fphar.2018.00110

Uncovering the signaling pathway behind extracellular guanine-induced activation of NO system: new perspectives in memory-related disorders

  • 1Department of Medical, Oral and Biotechnological Sciences, Università degli Studi "G. d'Annunzio" Chieti - Pescara, Italy
  • 2Aging Research Center, Ce.S.I., “G. d’Annunzio University Foundation, Chieti-Pescara, Italy
  • 3Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy
  • 4Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Italy
  • 5Department of Bio-Medical Sciences, University of Catania, Italy

Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; ii) the activation of this pathway occurs in a pertussis-toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory-related disorders.

Keywords: Guanine, L-NAME, Nitric Oxide, cGMP, ERK, SH-SY5Y cell line

Received: 15 Nov 2017; Accepted: 31 Jan 2018.

Edited by:

Kenneth A. Jacobson, National Institutes of Health (NIH), United States

Reviewed by:

Martina Schmidt, University of Groningen, Netherlands
FABIO TASCEDDA, Department of Life Sciences University of Modena, Italy  

Copyright: © 2018 Zuccarini, Giuliani, Frinchi, Mudò, Serio, Belluardo, Buccella, Carluccio, Condorelli, Caciagli, Ciccarelli and Di Iorio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Mariachiara Zuccarini, Università degli Studi "G. d'Annunzio" Chieti - Pescara, Department of Medical, Oral and Biotechnological Sciences, Via dei Vestini, 29, Chieti, 66100, Italy,
Prof. Francesco Caciagli, Università degli Studi "G. d'Annunzio" Chieti - Pescara, Department of Medical, Oral and Biotechnological Sciences, Via dei Vestini, 29, Chieti, 66100, Italy,