The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death

doi:10.1016/0167-5699(95)80045-X

Immunology Today

Volume 16, Issue 11, November 1995, Pages 524-528

Immunology Today

https://doi.org/10.1016/0167-5699(95)80045-X Get rights and content

Abstract

Many immune and inflammatory cells express a plasma membrane receptor for extracellular ATP, termed the P2Z purinoceptor, which appears to be coupled to a plasma membrane pore. The physiological role of such a molecule is generally unknown, except for the striking susceptibility to ATP-mediated cytotoxicity that it confers. The receptor is upregulated in human monocytes by interferon γ and is also expressed during macrophage differentiation. Here, Francesco Di Virgilio discusses recent information on this receptor, and suggests a possible role for it in the immune and inflammatory response.

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The P2X7 receptor in mood disorders: Emerging target in immunopsychiatry, from bench to bedside
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Citation Excerpt :
Moreover, the P2X7R forms a pore, also known as macropore, which can reach a diameter of ∼8.5 Å and allows the passage of hydrophilic macromolecules of a size up to 900 Da. The macromolecule most commonly used for in vitro experiments addressing the pore forming capacity is YO-PRO-1, a 376 Da fluorescent dye with a cross-section size of about 7.0 Å (Di Virgilio, 1995; Di Virgilio et al., 2018). P2X7R macropore formation also depends on TMEM16F, a membranous dual Ca2+-dependent phospholipid scramblase and Ca2+-activated ion channel (Dunning et al., 2021).
Psychiatric disorders are among the most burdensome disorders worldwide. Though therapies have evolved over the last decades, treatment resistance still affects many patients. Recently, neuroimmune systems have been identified as important factors of mood disorder biology. The underlying dysregulation in neuroimmune cross-talk is driven by genetic risk factors and accumulating adverse environmental influences like chronic psychosocial stress. These result in a cluster of proinflammatory cytokines and quantitative and functional changes of immune cell populations (e.g., microglia, monocytes, T cells), varying by disease entity and state. Among the emerging immune targets, purinergic signalling revolving around the membranous and ATP specific P2X7 receptor (P2X7R) has gained wider attention and clinical studies making use of antagonistic drugs are on-going. Still, no clinically meaningful applications have been identified so far. A major problem is the often overly simplified approach taken to translate findings from bench to bedside. Therefore, the present review focuses on purinergic signalling via P2X7R in the context of recent advances in immunopsychiatric mood disorder research. Our aim is to provide an overview of the current P2X7R-related findings, from bench to bedside. First, we summarize the characteristics of purinergic signalling and P2X7R, followed by a depiction of genetic and clinical data connecting P2X7R to mood disorders. We close with our perspective on current developments and discuss changes necessary to translate the evident potential of P2X7R signalling modulation into meaningful clinical application.
This article is part of the Special Issue on ‘Purinergic Signaling: 50 years’.
Extracellular ATP: A powerful inflammatory mediator in the central nervous system
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Nucleotides play a crucial role in extracellular signaling across species boundaries. All the three kingdoms of life (Bacteria, Archea and Eukariota) are responsive to extracellular ATP (eATP) and many release this and other nucleotides. Thus, eATP fulfills different functions, many related to danger-sensing or avoidance reactions. Basically all living organisms have evolved sensors for eATP and other nucleotides with very different affinity and selectivity, thus conferring a remarkable plasticity to this signaling system. Likewise, different intracellular transduction systems were associated during evolution to different receptors for eATP. In mammalian evolution, control of intracellular ATP (iATP) and eATP homeostasis has been closely intertwined with that of Ca²⁺, whether in the extracellular milieu or in the cytoplasm, establishing an inverse reciprocal relationship, i.e. high extracellular Ca²⁺ levels are associated to negligible eATP, while low intracellular Ca²⁺ levels are associated to high eATP concentrations. This inverse relationship is crucial for the messenger functions of both molecules. Extracellular ATP is sensed by specific plasma membrane receptors of widely different affinity named P2 receptors (P2Rs) of which 17 subtypes are known. This confers a remarkable plasticity to P2R signaling. The central nervous system (CNS) is a privileged site for purinergic signaling as all brain cell types express P2Rs. Accruing evidence suggests that eATP, in addition to participating in synaptic transmission, also plays a crucial homeostatic role by fine tuning microglia, astroglia and oligodendroglia responses. Drugs modulating the eATP concentration in the CNS are likely to be the new frontier in the therapy of neuroinflammation.
This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.
Rethinking purinergic concepts and updating the emerging role of P2X7 and P2X4 in amyotrophic lateral sclerosis
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The topic of the present review regards the ubiquitous and phylogenetically most ancient prototype of intercellular signaling, the one mediated by extracellular nucleosides and nucleotides, bearing a strong influence on pathophysiological processes in the nervous system. Not by chance, purine and pyrimidine molecules are the most prevalent and ubiquitous chemical messengers in the animal and plant kingdoms, operating through a large plethora of purinergic metabolizing enzymes, P1 and P2 receptors, nucleoside and nucleotide channels and transporters. Because ectonucleotidases degrade the agonists of P2 receptors while simultaneously generate the agonists for P1 receptors, and because several agonists, or antagonists, simultaneously bind and activate, or inhibit, more than one receptor subtype, it follows that an all-inclusive “purinergic network” perspective should be better considered when looking at purinergic actions. This becomes particularly crucial during pathological conditions as for instance amyotrophic lateral sclerosis, where the contribution of purinergic signaling has been demonstrated to differ according to each target cell phenotype and stage of disease progression.
Here we will present some newly updated results about P2X7 and P2X4 as the most thoroughly investigated P2 receptors in amyotrophic lateral sclerosis, being aware that the comprehension of their actions is still in progress, and that the purinergic rationale for studying this disease must be however wide-ranging and all-inclusive.
This article is part of the Special Issue on ‘Purinergic Signaling: 50 years’.
Combined drug triads for synergic neuroprotection in retinal degeneration
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This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson’s disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.
P2X7 receptor is essential for cross-dressing of bone marrow-derived dendritic cells
2021, iScience
T cell activation requires the processing and presentation of antigenic peptides in the context of a major histocompatibility complex (MHC complex). Cross-dressing is a non-conventional antigen presentation mechanism, involving the transfer of preformed peptide/MHC complexes from whole cells, such as apoptotic cells (ACs) to the cell membrane of professional antigen-presenting cells (APCs), such as dendritic cells (DCs). This is an essential mechanism for the induction of immune response against viral antigens, tumors, and graft rejection, which until now has not been clarified. Here we show for first time that the P2X7 receptor (P2X7R) is crucial to induce cross-dressing between ACs and Bone-Marrow DCs (BMDCs). In controlled ex vivo assays, we found that the P2X7R in both ACs and BMDCs is required to induce membrane and fully functional peptide/MHC complex transfer to BMDCs. These findings show that acquisition of ACs-derived preformed antigen/MHC-I complexes by BMDCs requires P2X7R expression.
Dissecting activation steps in P2X7 receptors
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P2X7 receptors are trimeric ion channels activated by extracellular ATP. Upon activation, they trigger cytolysis and apoptosis but also control cell proliferation. To shed more light on channel gating and the underlying function of the individual subunits, receptors of concatenated subunits were built containing a defined number of functional binding sites. The currents evoked by ATP were obtained in the outside-out configuration of the patch-clamp technique, and steady-state activation, as well as time courses, were analyzed. Our results show that each occupied binding site contributes to channel activation. While the occupation of a single binding site can already activate the channels, three bound ligands maximally stabilize the open state. Hence, P2X7 receptors can be described by a stepwise activation process.

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¹: Franceso Di Virgilio is at the Institute of General Pathology, University of Ferrara, Via Borsari, 46, I-44100 Ferrara, Italy.

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The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death

Abstract

Pharmacol. Ther.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Invest. Dermatol.

Blood

Arch. Biochem. Biophys.

Immunol. Today

Cell. Immunol.

Blood

J. Biol. Chem.

Am. J. Physiol.

Pharmacol. Rev.

Nature

J. Immunol.