Guanosine Mechanisms of Action: Toward Molecular Targets

Massari, Caio M.; Zuccarini, Mariachiara; Iorio, Patrizia Di; Tasca, Carla I.

doi:10.3389/fphar.2021.653146

Cited by 15 publications

(12 citation statements)

References 53 publications

(79 reference statements)

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“…Importantly, it has been recently demonstrated that ADO is able to displace [ 3 H]GUO binding with a potency order similar to GUO [7] and that GUO-induced effects require both A 1 R and A 2A R co-expression. It was indeed evidenced that GUO may act as a negative allosteric modulator of A 2A R only when A 1 R is present [10,19].…”

Section: Introductionmentioning

confidence: 95%

Guanosine modulates K+ membrane currents in SH-SY5Y cells: involvement of adenosine receptors

Gambino

Giglia

Gallo

et al. 2022

Pflugers Arch - Eur J Physiol

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Guanosine (GUO), widely considered a key signaling mediator, is implicated in the regulation of several cellular processes. While its interaction with neural membranes has been described, GUO still is an orphan neuromodulator. It has been postulated that GUO may eventually interact with potassium channels and adenosine (ADO) receptors (ARs), both particularly important for the control of cellular excitability. Accordingly, here, we investigated the effects of GUO on the bioelectric activity of human neuroblastoma SH-SY5Y cells by whole-cell patch-clamp recordings. We first explored the contribution of voltage-dependent K+ channels and, besides this, the role of ARs in the regulation of GUO-dependent cellular electrophysiology. Our data support that GUO is able to specifically modulate K+-dependent outward currents over cell membranes. Importantly, administering ADO along with GUO potentiates its effects. Overall, these results suggested that K+ outward membrane channels may be targeted by GUO with an implication of ADO receptors in SH-SY5Y cells, but also support the hypothesis of a functional interaction of the two ligands. The present research runs through the leitmotif of the deorphanization of GUO, adding insight on the interplay with adenosinergic signaling and suggesting GUO as a powerful modulator of SH-SY5Y excitability.

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Section: Introductionmentioning

confidence: 95%

Guanosine modulates K+ membrane currents in SH-SY5Y cells: involvement of adenosine receptors

Gambino

Giglia

Gallo

et al. 2022

Pflugers Arch - Eur J Physiol

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“…Guanosine (GUO) belongs to the family of the guanine-based purines (GBPs), which comprises other pharmacologically active molecules such as guanosine triphosphate and monophosphate (GTP and GMP, respectively), and the GUO metabolite, guanine (GUA). Numerous studies have shown that GBPs are neuroprotective agents contributing to nervous tissue repair upon brain injury (reviewed in [ 105 , 152 , 153 ]). GUO, in particular, exhibits anticonvulsant, antiparkinsonian, anxiolytic and antidepressant effects [ 152 , 153 ].…”

Section: Influence Of the Purinergic Signaling On The Main Functions ...mentioning

confidence: 99%

“…Numerous studies have shown that GBPs are neuroprotective agents contributing to nervous tissue repair upon brain injury (reviewed in [ 105 , 152 , 153 ]). GUO, in particular, exhibits anticonvulsant, antiparkinsonian, anxiolytic and antidepressant effects [ 152 , 153 ]. Additionally, some findings from our group have shown that GUO can stimulate the efflux of cholesterol and the expression of the ApoE in rat brain-cultured astrocytes and in C6 rat glioma cells by the involvement of the PI3K/ERK1/2 pathway [ 154 ].…”

Section: Influence Of the Purinergic Signaling On The Main Functions ...mentioning

confidence: 99%

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Passarella

Ronci

Liberto

et al. 2022

IJMS

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Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The “cholesterol shuttle” is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Niemann–Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol–purine reciprocal control could hopefully promote further research.

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“…Guo effects are mediated by A1 activation and negative modulation of the A2AR receptor. Moreover, Guo requires both A1R and A2AR coexpression in the form of the A1R-A2AR heteromer [189]. Adenosine receptors are broadly distributed in brain vessels, platelets, and neutrophilic granulocytes and regulate every step of endothelial-related inflammatory processes and vasodilatation [190,191].…”

Section: Current Challenges and Limitations Of Guanosine Application In Ischemic Strokementioning

confidence: 99%

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

Chojnowski

Opiełka

Nazar

et al. 2021

IJMS

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Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.

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Guanosine Mechanisms of Action: Toward Molecular Targets

Cited by 15 publications

References 53 publications

Guanosine modulates K+ membrane currents in SH-SY5Y cells: involvement of adenosine receptors

Guanosine modulates K+ membrane currents in SH-SY5Y cells: involvement of adenosine receptors

Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

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