The Elusive P2X7 Macropore
Open accessAbstract
ATP, which is released under pathological conditions and is considered a damage-associated molecular pattern (DAMP), activates P2X7 receptors (P2X7Rs), trimeric plasma membrane ion channels selective for small cations. P2X7Rs are partners in NOD-like receptor containing a pyrin (NLRP3) inflammasome activation and promoters of tumor cell growth. P2X7R overstimulation triggers the ATP-dependent opening of a nonselective plasma membrane pore, known as a 'macropore', which allows fluxes of large hydrophilic molecules. The pathophysiological functions of P2X7R are thought to be dependent on activation of this conductance pathway, yet its molecular identity is unknown. Recent reports show that P2X7R permeability to organic solutes is an early and intrinsic property of the channel itself. A better understanding of P2X7R-dependent changes in plasma membrane permeability will allow a rationale development of novel anti-inflammatory and anticancer drugs.
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The P2X7 receptor is a trimeric ionotropic receptor with low affinity for ATP (EC50 around 0.3-1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules.
“The P2X7 receptor is a trimeric ionotropic receptor that belongs to the P2X family of purinergic receptors, presenting low affinity for ATP (EC50 around 0.3–1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules [62–64].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [64]
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P2X7 Receptor in Hematological Malignancies
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Cáceres, F. T., Gaspari, T. A., Hossain, M. A., & Samuel, C. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137074 · Cited by 25 · see citing works
Kozlovskiy, S., Pislyagin, Е. А., Menchinskaya, E. S., Chingizova, E. A., Sabutski, Y. E., Полоник, С. Г., Николаевна, Л. Г., & Aminin, D. L. (2023) · Toxins · doi:10.3390/toxins15010047 · Cited by 25 · see citing works
Manfredini, M., Giuliani, A. L., Ruina, G., Gafà, R., Bosi, C., Zoppas, E., Virgilio, F. D., & Bettoli, V. (2019) · Dermatology · doi:10.1159/000502026 · Cited by 25 · see citing works
The Multifaceted Role of P2X7R in Microglia and Astrocytes
Bedetta, M., Pizzo, P., & Lia, A. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04502-y · Cited by 27 · see citing works
Carluccio, M., Zuccarini, M., Ziberi, S., Giuliani, P., Morabito, C., Mariggiò, M. A., Lonardo, M. T., Adinolfi, E., Orioli, E., Iorio, P. D., et al. (2019) · Stem Cell Reviews and Reports · doi:10.1007/s12015-019-09883-6 · Cited by 24 · see citing works
Wang, K., Sun, M., Juan, Z., Zhang, J., Sun, Y., Wang, G., Wang, C., Li, Y., Kong, W., Fan, L., et al. (2022) · Behavioural Neurology · doi:10.1155/2022/3777351 · Cited by 24 · see citing works
Purinergic receptors modulators: An emerging pharmacological tool for disease management
Mahmood, A., & Iqbal, J. (2022) · Medicinal Research Reviews · doi:10.1002/med.21888 · Cited by 24 · see citing works
Bergamin, L. S., Penolazzi, L., Lambertini, E., Falzoni, S., Sarti, A. C., Molle, C. M., Gendron, F., BONIS, P. D., Virgilio, F. D., & Piva, R. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29891 · Cited by 23 · see citing works
eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases
Panicucci, C., Raffaghello, L., Bruzzone, S., Baratto, S., Principi, E., Minetti, C., Gazzerro, E., & Bruno, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21175963 · Cited by 24 · see citing works
- Authors
- Di Virgilio, F., Schmalzing, G., & Markwardt, F.
- Affiliations
- RWTH Aachen University (DE)
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 28
- Issue
- 5
- Pages
- 392-404
- ISSN
- 0962-8924 (ISSN-L)
- OpenAlex
- W2787249947
- Cited by
- 279
- References
- 96
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 41 · 2023: 44 · 2022: 31 · 2021: 30 · 2020: 33 · 2019: 37 · 2018: 17
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Trends in Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, cc-by-nc-nd)
- Funders
- Italian Association for Cancer Research (13025, 18581)
- Ministry of Health of Italy (RF-2011-02348435)
- University of Ferrara
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- P2X7 receptor, ATP, plasma membrane permeability, NLRP3 inflammasome, damage-associated molecular patterns, ion channel conductance, anti-inflammatory agents, anticancer agents
- MeSH terms
- Alarmins, NLR Family, Pyrin Domain-Containing 3 Protein, Adenosine Triphosphate, Cell Membrane Permeability, Humans, Neoplasms, Signal Transduction, Cell Proliferation, Receptors, Purinergic P2X7, Inflammasomes
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