{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:08:56Z","timestamp":1771337336317,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FONDECYT Regular","award":["1231554 (CA-C)"],"award-info":[{"award-number":["1231554 (CA-C)"]}]},{"name":"FONDECYT Regular","award":["1220680 (EL-S)"],"award-info":[{"award-number":["1220680 (EL-S)"]}]},{"name":"FONDECYT de Iniciaci\u00f3n en investigaci\u00f3n","award":["11231081 (CB-A)"],"award-info":[{"award-number":["11231081 (CB-A)"]}]},{"name":"FONDEQUIP EQM","award":["150069"],"award-info":[{"award-number":["150069"]}]},{"name":"FONDEQUIP EQM","award":["190130"],"award-info":[{"award-number":["190130"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The purinergic ionotropic receptor P2X7 stands out from other members of the P2X family due to its ability to form a macropore, activate multiple intracellular signaling pathways, and, as more recently reported, to mediate scavenger activity toward apoptotic cells. In addition, P2X7 exhibits a high number of single nucleotide polymorphisms (SNPs) and splice variants, several of which have been shown to impair ATP-mediated macropore formation. The aim of this study was to determine whether specific SNPs or deletion variants that have lost channel conductance or macropore activity retain other reported P2X7 functions. To address this, we analyzed the following variants: P2X7A (wild-type), P2X7B (unable to activate the macropore), P2X7 T283M (lacking conductance and macropore formation), P2X7 with N-terminal deletion (\u2206N; deficient in signal transduction), and P2X7 DN (dominant-negative double mutant W167A\/C168A, lacking all known activities). We evaluated calcium influx, macropore formation, ERK and p38 signaling, and scavenger activity. Our results indicate that macropore formation depends on channel conductance, in contrast to what has been previously reported for P2X7B. Moreover, all modifications tested impaired signaling pathway activation. Strikingly, none of the mutations affected receptor-mediated phagocytic activity. These findings suggest that loss of conductance or macropore formation does not necessarily entail loss of other P2X7 functions, and our data reveals a functional independence between scavenger activity and the canonical roles of P2X7 (channel\/macropore, MAPKs). This modular view provides a framework to reconcile the apparently discordant phenotypes of P2X7 variants observed across diverse pathophysiological settings.<\/jats:p>","DOI":"10.3390\/ijms27041922","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:15:35Z","timestamp":1771334135000},"page":"1922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rat P2X7 Receptor Show Functional Independence Between Macropore Formation and Scavenger Activity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-0470","authenticated-orcid":false,"given":"Javier","family":"Mena","sequence":"first","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6487-5648","authenticated-orcid":false,"given":"El\u00edas","family":"Leiva-Salcedo","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9985-0599","authenticated-orcid":false,"given":"Natalia","family":"Araya-Dapremont","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8451-8754","authenticated-orcid":false,"given":"Francisco","family":"Bravo-Cabezas","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3866-6854","authenticated-orcid":false,"given":"Ana Jane","family":"Villa","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2901-2952","authenticated-orcid":false,"given":"Geraldine","family":"Vivanco-Duarte","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1125-7226","authenticated-orcid":false,"given":"\u00c1ngel","family":"Mej\u00eda","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"},{"name":"Instituto de Investigaciones en Microbiolog\u00eda, Facultad de Ciencias, Universidad Nacional Aut\u00f3noma de Honduras, Tegucigalpa 11101, Honduras"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Galarce-Keidong","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mat\u00edas","family":"Lee","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0190-6034","authenticated-orcid":false,"given":"Francisca","family":"Espinola-Gonzalez","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1693-553X","authenticated-orcid":false,"given":"Nelly","family":"Nu\u00f1ez-Rojas","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7651-5089","authenticated-orcid":false,"given":"Nayiberg","family":"Varas","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Mella-Torres","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Pablo","family":"Huidobro-Toro","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-6329","authenticated-orcid":false,"given":"Kevin","family":"Maisey","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. 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Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1587-4179","authenticated-orcid":false,"given":"Alejandro","family":"Escobar","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Ciencias Odontol\u00f3gicas, Facultad de Odontolog\u00eda, Universidad de Chile, Olivos 943, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6160-9563","authenticated-orcid":false,"given":"Carlos","family":"Barrera-Avalos","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-6077","authenticated-orcid":false,"given":"Claudio","family":"Acu\u00f1a-Castillo","sequence":"additional","affiliation":[{"name":"Centro de Biotecnolog\u00eda Acu\u00edcola, Universidad de Santiago de Chile, Av. Libertador Bernardo O\u2019Higgins 3363, Santiago 9170022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.immuni.2017.06.020","article-title":"The P2X7 Receptor in Infection and Inflammation","volume":"47","author":"Sarti","year":"2017","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12974-018-1205-6","article-title":"Serum amyloid A primes microglia for ATP-dependent interleukin-1\u03b2 release","volume":"15","author":"Facci","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bibi\u010d, L., and Stokes, L. (2020). Revisiting the Idea That Amyloid-\u03b2 Peptide Acts as an Agonist for P2X7. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.00166"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.jid.2022.10.020","article-title":"Cathelicidin LL-37 Activates Human Keratinocyte Autophagy through the P2X7, Mechanistic Target of Rapamycin, and MAPK Pathways","volume":"143","author":"Ikutama","year":"2023","journal-title":"J. Investig. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1042\/bj20030585","article-title":"P2X7 receptor activates extracellular signal-regulated kinases ERK1 and ERK2 independently of Ca2+ influx","volume":"374","author":"Amstrup","year":"2003","journal-title":"Biochem. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15571","DOI":"10.1016\/S0021-9258(18)82295-5","article-title":"Dissociation of the pore-forming and phospholipase D activities stimulated via P2z purinergic receptors in BAC1.2F5 macrophages. Product inhibition of phospholipase D enzyme activity","volume":"268","author":"Dubyak","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1194\/jlr.M500408-JLR200","article-title":"Coupling of two pools of P2X7 receptors to distinct intracellular signaling pathways in rat submandibular gland","volume":"47","author":"Tandel","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kopp, R., Krautloher, A., Ram\u00edrez-Fern\u00e1ndez, A., and Nicke, A. (2019). P2X7 Interactions and Signaling\u2014Making Head or Tail of It. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00183"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1083\/jcb.138.3.697","article-title":"Spontaneous cell fusion in macrophage cultures expressing high levels of the P2Z\/P2X7 receptor","volume":"138","author":"Chiozzi","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref_10","first-page":"1264","article-title":"P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration","volume":"25","author":"Pellegatti","year":"2011","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103520","DOI":"10.1016\/j.isci.2021.103520","article-title":"P2X7 receptor is essential for cross-dressing of bone marrow-derived dendritic cells","volume":"24","author":"Imarai","year":"2021","journal-title":"IScience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1182\/blood-2009-11-251744","article-title":"The P2X7-nonmuscle myosin membrane complex regulates phagocytosis of nonopsonized particles and bacteria by a pathway attenuated by extracellular ATP","volume":"115","author":"Gu","year":"2010","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.bbadis.2018.01.012","article-title":"The scavenger activity of the human P2X7 receptor differs from P2X7 pore function by insensitivity to antagonists, genetic variation and sodium concentration: Relevance to inflammatory brain diseases","volume":"1864","author":"Ou","year":"2018","journal-title":"Biochim. Et Biophys. Acta-Mol. Basis Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.tcb.2018.01.005","article-title":"The Elusive P2X7 Macropore","volume":"28","author":"Schmalzing","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11135","DOI":"10.1074\/jbc.M010353200","article-title":"A Glu-496 to Ala Polymorphism Leads to Loss of Function of the Human P2X7 Receptor","volume":"276","author":"Gu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pegoraro, A., Grignolo, M., Ruo, L., Ricci, L., and Adinolfi, E. (2024). P2X7 Variants in Pathophysiology. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126673"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11302-017-9598-8","article-title":"N-terminal tagging of human P2X7 receptor disturbs calcium influx and dye uptake","volume":"14","author":"Dreisig","year":"2018","journal-title":"Purinergic Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1124\/pr.113.008003","article-title":"The p2x7 receptor channel: Recent developments and the use of p2x7 antagonists in models of disease","volume":"66","author":"Bartlett","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s11302-024-10039-6","article-title":"Role of the P2X7 receptor in breast cancer progression","volume":"21","author":"Du","year":"2025","journal-title":"Purinergic Signal."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1042\/CS20201352","article-title":"P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model","volume":"135","author":"Cuthbertson","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"p 102346","DOI":"10.1016\/j.coph.2022.102346","article-title":"Purinergic signalling in graft-versus-host disease","volume":"68","author":"Sluyter","year":"2023","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1164\/rccm.200607-970OC","article-title":"A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis","volume":"175","author":"Fernando","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.meegid.2017.05.003","article-title":"Genetic polymorphisms of the P2X7 gene associated with susceptibility to and prognosis of pulmonary tuberculosis","volume":"53","author":"Zheng","year":"2017","journal-title":"Infect. Genet. Evol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1124\/mol.65.3.646","article-title":"Selective Knock-Down of P2X7 ATP Receptor Function by Dominant-Negative Subunits","volume":"65","author":"Raouf","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_25","first-page":"152625","article-title":"Lipopolysaccharide inhibits the channel activity of the P2X7 receptor","volume":"2011","author":"Coddou","year":"2011","journal-title":"Mediat. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.4049\/jimmunol.1101178","article-title":"P2X7 Is a Scavenger Receptor for Apoptotic Cells in the Absence of Its Ligand, Extracellular ATP","volume":"187","author":"Gu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-cuesta, M.\u00c1., Blanch-ruiz, M.A., Ortega-luna, R., S\u00e1nchez-l\u00f3pez, A., and \u00c1lvarez, \u00c1. (2020). Structural and Functional Basis for Understanding the Biological Significance of P2X7 Receptor. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228454"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sluyter, R., Adriouch, S., Fuller, S.J., Nicke, A., Sophocleous, R.A., and Watson, D. (2023). Animal Models for the Investigation of P2X7 Receptors. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24098225"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1124\/mol.54.1.22","article-title":"Isoquinolines as antagonists of the P2X7 nucleotide receptor: High selectivity for the human versus rat receptor homologues","volume":"54","author":"Humphreys","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1189\/jlb.1203648","article-title":"The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho","volume":"75","author":"Pfeiffer","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41419-021-04378-0","article-title":"P2X7 promotes metastatic spreading and triggers release of miRNA-containing exosomes and microvesicles from melanoma cells","volume":"12","author":"Pegoraro","year":"2021","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1922\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:16:57Z","timestamp":1771334217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1922"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041922"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041922","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]}}}