Reactive Oxygen Species Potentiate the P2X(2) Receptor Activity through Intracellular Cys(430)

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dc.contributor.authorCoddou, Claudio
dc.contributor.authorCodocedo, Juan F.
dc.contributor.authorLi, Shuo
dc.contributor.authorLillo, Juan G.
dc.contributor.authorAcuna Castillo, Claudio
dc.contributor.authorBull, Paulina
dc.contributor.authorStojilkovic, Stanko S.
dc.contributor.authorHuidobro Toro, J. Pablo
dc.date.accessioned2024-01-10T14:21:31Z
dc.date.available2024-01-10T14:21:31Z
dc.date.issued2009
dc.description.abstractP2X receptor channels (P2XRs) are allosterically modulated by several compounds, mainly acting at the ectodomain of the receptor. Like copper, mercury, a metal that induces oxidative stress in cells, also stimulates the activity of P2X(2)R and inhibits the activity of P2X(4)R. However, the mercury modulation is not related to the extracellular residues critical for copper modulation. To identify the site(s) for mercury action, we generated two chimeras using the full size P2X(2) subunit, termed P2X(2a), and a splice variant lacking a 69 residue segment in the C terminal, termed P2X(2b), as the donors for intracellular and transmembrane segments and the P2X(4) subunit as the donor for ectodomain segment of chimeras. The potentiating effect of mercury on ATP-induced current was preserved in Xenopus oocytes expressing P2X(4/2a) chimera but was absent in oocytes expressing P2X(4/2b) chimera. Site-directed mutagenesis experiments revealed that the Cys(430) residue mediates effects of mercury on the P2X(2a)R activity. Because mercury could act as an oxidative stress inducer, we also tested whether hydrogen peroxide (H2O2) and mitochondrial stress inducers myxothiazol and rotenone mimicked mercury effects. These experiments, done in both oocytes and human embryonic kidney HEK293 cells, revealed that these compounds potentiated the ATP-evoked P2X(2a)R and P2X(4/2a)R currents but not P2X(2b)R and P2X(2a)-C430A and P2X(2a)-C430S mutant currents, whereas antioxidants dithiothreitrol and N-acetylcysteine prevented the H2O2 potentiation. Alkylation of Cys(430) residue with methylmethane-thiosulfonate also abolished the mercury and H2O2 potentiation. Altogether, these results are consistent with the hypothesis that the Cys(430) residue is an intracellular P2X(2a)R redox sensor.
dc.description.funderFondo de Investigacion Avanzada en Areas Prioritarias
dc.description.funderNational Institute of Child Health and Human Development/National Institutes of Health
dc.description.funderEUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
dc.description.funderEUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT
dc.format.extent8 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1523/JNEUROSCI.2096-09.2009
dc.identifier.issn0270-6474
dc.identifier.pubmedidMEDLINE:19793987
dc.identifier.urihttps://doi.org/10.1523/JNEUROSCI.2096-09.2009
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79691
dc.identifier.wosidWOS:000270363300028
dc.information.autorucCiencias Biológicas;Bull P;S/I;99734
dc.information.autorucCiencias Biológicas;Coddou C;S/I;9297
dc.information.autorucCiencias Biológicas;Codocedo JF;S/I;189146
dc.information.autorucCiencias Biológicas;Huidobro-Toro JP;S/I;98862
dc.information.autorucCiencias Biológicas;Lillo JG;S/I;6569
dc.issue.numero39
dc.language.isoen
dc.nota.accesoSin adjunto
dc.pagina.final12291
dc.pagina.inicio12284
dc.publisherSOC NEUROSCIENCE
dc.revistaJOURNAL OF NEUROSCIENCE
dc.rightsregistro bibliográfico
dc.subjectGROWING ESCHERICHIA-COLI
dc.subjectSMOOTH-MUSCLE CELLS
dc.subjectHYDROGEN-PEROXIDE
dc.subjectHISTIDINE-RESIDUES
dc.subjectRESPIRATORY-CHAIN
dc.subjectRAT HEPATOCYTES
dc.subjectHEAVY-METALS
dc.subjectMODULATION
dc.subjectCHANNELS
dc.subjectMERCURY
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleReactive Oxygen Species Potentiate the P2X(2) Receptor Activity through Intracellular Cys(430)
dc.typeartículo
dc.volumen29
sipa.codpersvinculados99734
sipa.codpersvinculados9297
sipa.codpersvinculados189146
sipa.codpersvinculados98862
sipa.codpersvinculados6569
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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