Diadenosine Homodinucleotide Products of ADP-ribosyl Cyclases Behave as Modulators of the Purinergic Receptor P2X7

Bruzzone, Santina; Basile, Giovanna; Chothi, Madhu Parakkottil; Nobbio, Lucilla; Usai, Cesare; Jacchetti, Emanuela; Schenone, Angelo; Guse, Andreas H.; Virgilio, Francesco Di; Flora, Antonio De; Zocchi, Elena

doi:10.1074/jbc.m109.097964

Cited by 12 publications

(19 citation statements)

References 49 publications

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“…One example is that of the diadenosine diphosphate isomer P18, which both antagonizes P2X7 and activates P2Y 11 [14,81], demonstrating the need to test possible P2Y 11 agonistic and antagonistic compounds on all ATPbinding P2 receptors before drawing any conclusions about specificity.…”

Section: Selective P2y 11 Activation and Inhibitionmentioning

confidence: 99%

A critical look at the function of the P2Y11 receptor

Dreisig

Kornum

2016

Purinergic Signalling

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The P2Y 11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermore, some of the studies reported to date have methodological shortcomings, making it difficult to determine the function of P2Y 11 with certainty. In this review, we discuss the lack of a murine BP2Y 11 -like receptor^and highlight the limitations of the currently available methods used to investigate the P2Y 11 receptor. These methods include protein recognition with antibodies that show very little specificity, gene expression studies that completely overlook the existence of a fusion transcript between the adjacent PPAN gene and P2RY11, and agonists/antagonists reported to be specific for the P2Y 11 receptor but which have not been tested for activity on numerous other adenosine 5′-triphosphate (ATP)-binding receptors. We suggest a set of criteria for evaluating whether a dataset describes effects mediated by the P2Y 11 receptor. Following these criteria, we conclude that the current evidence suggests a role for P2Y 11 in immune activation with cell typespecific effects.

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Section: Selective P2y 11 Activation and Inhibitionmentioning

confidence: 99%

A critical look at the function of the P2Y11 receptor

Dreisig

Kornum

2016

Purinergic Signalling

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“…Using pharmacological inhibitors and siRNA technology, we demonstrated that the high [Ca 2+ ] i levels of the SC from CMT1A rats are causally determined by PMP22-related overexpression of the P2X7 purinoceptor, which is responsible for enhanced influx of extracellular Ca 2+ [Nobbio, 2009]. The addition of extracellular P18, at a 200 nM concentration, was able to downregulate the basal [Ca 2+ ] i levels of SC from CMT1A rats to values comparable to those measured in wild type SC [Bruzzone, 2010]. Thus, the activity of P18 and P24 as P2X7 modulators may be of potential therapeutic significance with different possible applications, in which targeting (either inhibiting or stimulating) P2X7 might prove a successful strategy.…”

Section: Other Topological Problems Related To Cd38 Productsmentioning

confidence: 77%

“…Indeed, in HEK293 stably transfected with P2X7, micromolar P24, but not P18, elicits the opening of P2X7 and the consequent slow and enhanced entry of extracellular Ca 2+ [Bruzzone, 2010]. Remarkably, both P24 and P18 proved to inhibit, with an IC 50 of 17.0 and 1.0 M, respectively, the ATP-induced [Ca 2+ ] i elevation and the consequent pore formation of P2X7.…”

Section: Other Topological Problems Related To Cd38 Productsmentioning

confidence: 95%

“…We recently identified P2X7 as the receptor/channel mediating the P24-triggered extracellular Ca 2+ influx [Bruzzone, 2010]. Indeed, in HEK293 stably transfected with P2X7, micromolar P24, but not P18, elicits the opening of P2X7 and the consequent slow and enhanced entry of extracellular Ca 2+ [Bruzzone, 2010].…”

Section: Other Topological Problems Related To Cd38 Productsmentioning

confidence: 99%

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Subcellular and Intercellular Traffic of NAD+, NAD+ Precursors and NAD+-Derived Signal Metabolites and Second Messengers: Old and New Topological Paradoxes

Bruzzone¹,

Guida²,

Sturla³

et al. 2012

messenger

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NAD + metabolism and regulation are still incompletely defined in their features. Specifically, several compartmentation problems, both subcellular and intercellular, have emerged in the past years. A topological paradox was identified in the CD38/NAD + /Cyclic ADP-ribose system which represents a means for achieving regulation of intracellular Calcium levels ([Ca 2+ ] i and of Ca 2+ -mediated cell functions. CD38, an ectoenzyme featuring ADP-ribosyl cyclase (ADPRC) activity, is known to catalyze the generation of as many as eight Ca 2+ -active signal metabolites, including cADPR, ADPR, NAADP and three adenine homodinucleotides (Ap2A and two isomers thereof, designated P18 and P24). The first paradox concerns the ectocellular conversion of NAD + to cADPR and the intracellular activity of cADPR as a potent Ca 2+ mobilizer from stores expressing ryanodine receptors/channels on the endoplasmic/sarcoplasmic reticulum. This topological inconsistency was solved with the identification of hexameric Connexin 43 hemichannels (Cx43 HC) as an equilibrative transport system for NAD + , and of redundant equilibrative, and especially concentrative, transport systems for cADPR. Other transporters for NAADP + , P18 and P24 are still unknown. In addition, NAD + itself and some of its derivatives were recognized to be agonists of purinergic receptors, e.g., P2Y 11 and P2X 7 , thereby affecting the [Ca 2+ ] i levels either through protein kinase A-and phospholipase C-mediated pathways or through direct influx of extracellular Ca 2+ , respectively. Finally, recent findings demonstrate that the enzymes involved in NAD + biosynthesis and some of the enzymes involved in the multiple pathways of NAD + utilization localize to distinct subcellular compartments of the same cell and, surprisingly, also to different cell types of the same organism. Therefore, NAD + biosynthesis from several precursors, collectively defined Vitamin B3 forms, is at the same time an organismal and a cellular process, whose individual steps may occur in different cells/tissues/organs. Thus, a paracrine crosstalk is activated via the exchange of intermediate metabolites in biological fluids (e.g., Nicotinamide mononucleotide and Nicotinamide riboside), and the eventual NAD + biosynthesis occurs in selected cells able to utilize it for the display of diverse, fundamental cell functions. These are driven by NAD + -consuming enzymes, as ADPRCs, mono ADP-ribosyltransferases, poly(ADP-ribose) polymerases and different sirtuins (NAD + -dependent protein deacetylases).

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“…In addition, P2Y11 is the only purinergic receptor coupled to both AC and phospholipase C [Qi et al, ]. We demonstrated that P18 behaves as an antagonist of P2X7 [Bruzzone et al, ]. Unlike P18, P24 is a partial agonist of P2X7, eliciting influx of extracellular Ca 2+ , without leading to pore formation [Bruzzone et al, ].…”

mentioning

confidence: 99%