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Cited by 249Adenosine and Purinergic SignalingPain Mechanisms and TreatmentsCalcium signaling and nucleotide metabolism

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The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

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Burnstock, Geoffrey, Knight, Gillian E.·2018·Purinergic Signalling
DOI 10.1007/s11302-017-9593-0PMC PMC5842154
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Abstract

Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.

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Figures

Fig. 1 Cell type-specific schema of ATP release and action. ATP (red triangles) can be released from the cell cytosol to the extracellular space (dashed red line) via pannexin 1 (Panx1) channels or connexin 43 (Cx43) hemichannels (pictured). Once in the extracellular space, this ATP acts as a paracrine transmitter, as can ATP released from nearby cells that are dead or dying (not shown). Extracellular ATP can activate P2 receptors, such as P2X7 receptors (P2X7R) (pictured), that depolarise the target cell but also activate an inflammatory response in immune cells (dashed gray line) with subsequent release of cytokines such as interleukin (IL)-1β that can act back at Panx1 and Cx43 to modulate their function (dashed gray lines). Activation of P2X7R also mediates the T cell responses (e.g. Ca2+ entry, IL-2 synthesis) and macrophage migration (not shown). (Reproduced from [15], with permission from Frontiers Media S.A. (via Open Access))
Fig. 1 Cell type-specific schema of ATP release and action. ATP (red triangles) can be released from the cell cytosol to the extracellular space (dashed red line) via pannexin 1 (Panx1) channels or connexin 43 (Cx43) hemichannels (pictured). Once in the extracellular space, this ATP acts as a paracrine transmitter, as can ATP released from nearby cells that are dead or dying (not shown). Extracellular ATP can activate P2 receptors, such as P2X7 receptors (P2X7R) (pictured), that depolarise the target cell but also activate an inflammatory response in immune cells (dashed gray line) with subsequent release of cytokines such as interleukin (IL)-1β that can act back at Panx1 and Cx43 to modulate their function (dashed gray lines). Activation of P2X7R also mediates the T cell responses (e.g. Ca2+ entry, IL-2 synthesis) and macrophage migration (not shown). (Reproduced from [15], with permission from Frontiers Media S.A. (via Open Access))CC BY · PubMed Central
Fig. 2 Altered regulation of calcium channels in brain tumours is part of neoplastic transformation. In the brain, the transformation of a normal cell into a tumour cell might be related to Ca2+ oscillations, and the homeostasis misbalance can define the malignant phenotype, which includes uncontrolled proliferation, enhanced migration and invasion and abnormal cell death. The activation of P2X7 receptors (P2X7R) leads to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase 1/2 (MEK1/2) activation. High P2X7R functionality and pore activity are linked to apoptosis/necrosis in glioma cells and better progression-free survival. (Reproduced from [55], with permission from the American Society for Pharmacology and Experimental Therapeutics)
Fig. 2 Altered regulation of calcium channels in brain tumours is part of neoplastic transformation. In the brain, the transformation of a normal cell into a tumour cell might be related to Ca2+ oscillations, and the homeostasis misbalance can define the malignant phenotype, which includes uncontrolled proliferation, enhanced migration and invasion and abnormal cell death. The activation of P2X7 receptors (P2X7R) leads to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase 1/2 (MEK1/2) activation. High P2X7R functionality and pore activity are linked to apoptosis/necrosis in glioma cells and better progression-free survival. (Reproduced from [55], with permission from the American Society for Pharmacology and Experimental Therapeutics)CC BY · PubMed Central
Fig. 3 Common disease mechanism by P2X7 receptor (P2X7R)-mediated pathways in central nervous system (CNS) disorders of different etiology. P2X7R are expressed on nerve terminals, astrocytes and microglia, and they are upregulated in various disease conditions. Stress signals such as hypoxia/ischemia (metabolic limitations), mechanical injury and bacterial or chemical toxins elicit the endogenous activation of P2X7R and lead to a self-amplifying ATP release and to further activation of P2X7R on neighbouring cells. Following the influx of Ca2+ through the receptor ion channel complex, P2X7R activation (i) releases glutamate from nerve terminals and astrocytes by both exocytotic and non-exocytotic mechanisms, which may give rise excitotoxicity; (ii) leads to the posttranslational processing of pro-interleukin-1β (pro-IL-1β) to the leaderless, mature IL-1β and to its further release by the NLRP3 inflammasome and that of other cytokines, which contribute to neuroinflammation; (iii) enhance reactive oxygen species (ROS) production and thereby aggravate protein misfolding and neuronal damage; (iv) leads directly or indirectly to cell death and the following reactive astrogliosis; and (v) directly or indirectly downregulates the production of brain-derived neurotrophic factor (BDNF) and the subsequent neuroplasticity. These key mechanisms could be manifested and contribute to disease pathology in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), status epilepticus (SE), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, pain and mood disorders in different forms and proportion, depending on the etiology. Abbreviations: GLU, glutamate, ROS, reactive oxygen species. (Reproduced from [92], with permission from Elsevier)
Fig. 3 Common disease mechanism by P2X7 receptor (P2X7R)-mediated pathways in central nervous system (CNS) disorders of different etiology. P2X7R are expressed on nerve terminals, astrocytes and microglia, and they are upregulated in various disease conditions. Stress signals such as hypoxia/ischemia (metabolic limitations), mechanical injury and bacterial or chemical toxins elicit the endogenous activation of P2X7R and lead to a self-amplifying ATP release and to further activation of P2X7R on neighbouring cells. Following the influx of Ca2+ through the receptor ion channel complex, P2X7R activation (i) releases glutamate from nerve terminals and astrocytes by both exocytotic and non-exocytotic mechanisms, which may give rise excitotoxicity; (ii) leads to the posttranslational processing of pro-interleukin-1β (pro-IL-1β) to the leaderless, mature IL-1β and to its further release by the NLRP3 inflammasome and that of other cytokines, which contribute to neuroinflammation; (iii) enhance reactive oxygen species (ROS) production and thereby aggravate protein misfolding and neuronal damage; (iv) leads directly or indirectly to cell death and the following reactive astrogliosis; and (v) directly or indirectly downregulates the production of brain-derived neurotrophic factor (BDNF) and the subsequent neuroplasticity. These key mechanisms could be manifested and contribute to disease pathology in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), status epilepticus (SE), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, pain and mood disorders in different forms and proportion, depending on the etiology. Abbreviations: GLU, glutamate, ROS, reactive oxygen species. (Reproduced from [92], with permission from Elsevier)CC BY · PubMed Central

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Metadata

Authors
Burnstock, G., & Knight, G. E.
Affiliations
  • The University of Melbourne (AU)
  • University College London (GB)
Corresponding author
Burnstock, Geoffrey
ORCID
Burnstock, Geoffrey
Venue
Purinergic Signalling
Publisher
Springer Science and Business Media LLC
Published
2017-11-21
Volume
14
Issue
1
Pages
1-18
ISSN
  • 1573-9538 (ISSN-L)
  • 1573-9546
DOI
10.1007/s11302-017-9593-0
PMC
PMC5842154
OpenAlex
W2768734810
Semantic Scholar
1aa37d0f163277fbeb968b6bb8cea0a8afcbe622
Cited by
248
References
228
Citations by year
2026: 13 · 2025: 20 · 2024: 22 · 2023: 25 · 2022: 28 · 2021: 48 · 2020: 52 · 2019: 27 · 2018: 13
FWCI
2.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Purinergic Signalling (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
University College London (UCL)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
P2X7 receptor, ATP, P2X7 receptor antagonists, inflammation, tumor progression, apoptosis, neurodegenerative diseases, mental illness, epilepsy, therapeutic target
MeSH terms
Animals, Humans, Inflammation, Neoplasms, Disease Progression, Receptors, Purinergic P2X7, Purinergic P2X Receptor Antagonists

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