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

Giuseppa Mudo', Rosa Maria Serio, Natale Belluardo, Mariachiara Zuccarini, Marzia Carluccio, Daniele F. Condorelli, Francesco Caciagli, Patrizia Di Iorio, Renata Ciccarelli, Silvana Buccella, Patricia Giuliani, Monica Frinchi

Risultato della ricerca: Article

2 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)110-
Numero di pagine15
RivistaFrontiers in Pharmacology
Volume9
Stato di pubblicazionePublished - 2018

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Memory Disorders
Guanine
Guanosine
Guanine Deaminase
NG-Nitroarginine Methyl Ester
Nucleoside Deaminases
Learning
Purine-Nucleoside Phosphorylase
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Purines
Pertussis Toxin
G-Protein-Coupled Receptors
Guanosine Triphosphate
Neuroblastoma
Short-Term Memory
Neurodegenerative Diseases
Cognition
Oral Administration
Parkinson Disease
Signal Transduction

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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Uncovering the signaling pathway behind extracellular guanine-induced activation of NO System: New perspectives in memory-related disorders. / Mudo', Giuseppa; Serio, Rosa Maria; Belluardo, Natale; Zuccarini, Mariachiara; Carluccio, Marzia; Condorelli, Daniele F.; Caciagli, Francesco; Di Iorio, Patrizia; Ciccarelli, Renata; Buccella, Silvana; Giuliani, Patricia; Frinchi, Monica.

In: Frontiers in Pharmacology, Vol. 9, 2018, pag. 110-.

Risultato della ricerca: Article

Mudo', G, Serio, RM, Belluardo, N, Zuccarini, M, Carluccio, M, Condorelli, DF, Caciagli, F, Di Iorio, P, Ciccarelli, R, Buccella, S, Giuliani, P & Frinchi, M 2018, 'Uncovering the signaling pathway behind extracellular guanine-induced activation of NO System: New perspectives in memory-related disorders', Frontiers in Pharmacology, vol. 9, pagg. 110-.
Mudo', Giuseppa ; Serio, Rosa Maria ; Belluardo, Natale ; Zuccarini, Mariachiara ; Carluccio, Marzia ; Condorelli, Daniele F. ; Caciagli, Francesco ; Di Iorio, Patrizia ; Ciccarelli, Renata ; Buccella, Silvana ; Giuliani, Patricia ; Frinchi, Monica. / Uncovering the signaling pathway behind extracellular guanine-induced activation of NO System: New perspectives in memory-related disorders. In: Frontiers in Pharmacology. 2018 ; Vol. 9. pagg. 110-.
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abstract = "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.",
author = "Giuseppa Mudo' and Serio, {Rosa Maria} and Natale Belluardo and Mariachiara Zuccarini and Marzia Carluccio and Condorelli, {Daniele F.} and Francesco Caciagli and {Di Iorio}, Patrizia and Renata Ciccarelli and Silvana Buccella and Patricia Giuliani and Monica Frinchi",
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T1 - Uncovering the signaling pathway behind extracellular guanine-induced activation of NO System: New perspectives in memory-related disorders

AU - Mudo', Giuseppa

AU - Serio, Rosa Maria

AU - Belluardo, Natale

AU - Zuccarini, Mariachiara

AU - Carluccio, Marzia

AU - Condorelli, Daniele F.

AU - Caciagli, Francesco

AU - Di Iorio, Patrizia

AU - Ciccarelli, Renata

AU - Buccella, Silvana

AU - Giuliani, Patricia

AU - Frinchi, Monica

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10447/283477

UR - https://www.frontiersin.org/articles/10.3389/fphar.2018.00110/full

M3 - Article

VL - 9

SP - 110-

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

ER -