P2X7 receptor-Pannexin1 complex: pharmacology and signaling

dc.creatorIglesias, R.
dc.creatorLocovei, S.
dc.creatorRoque, A.
dc.creatorAlberto, A. P.
dc.creatorDahl, G.
dc.creatorSpray, D. C.
dc.creatorScemes, E.
dc.date2019-04-02T15:23:10Z
dc.date2019-04-02T15:23:10Z
dc.date2008
dc.date.accessioned2023-09-26T23:15:31Z
dc.date.available2023-09-26T23:15:31Z
dc.identifierIGLESIAS, R. et al. P2X7 receptor-Pannexin1 complex: pharmacology and signaling. Am J Physiol Cell Physiol., v. 295, p. C752–C760, 2008.
dc.identifier0363-6143
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/32332
dc.identifier10.1152/ajpcell.00228.2008
dc.identifier1522-1563
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8888580
dc.descriptionPannexin 1 (Panx1), an ortholog to invertebrate innexin gap junctions, has recently been proposed to be the pore induced by P2X(7) receptor (P2X(7)R) activation. We explored the pharmacological action of compounds known to block gap junctions on Panx1 channels activated by the P2X(7)R and the mechanisms involved in the interaction between these two proteins. Whole cell recordings revealed distinct P2X(7)R and Panx1 currents in response to agonists. Activation of Panx1 currents following P2X(7)R stimulation or by membrane depolarization was blocked by Panx1 small-interfering RNA (siRNA) and with mefloquine > carbenoxolone > flufenamic acid. Incubation of cells with KN-62, a P2X(7)R antagonist, prevented current activation by 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP). Membrane permeabilization to dye induced by BzATP was also prevented by Panx1 siRNA and by carbenoxolone and mefloquine. Membrane permeant (TAT-P2X(7)) peptides, provided evidence that the Src homology 3 death domain of the COOH-terminus of the P2X(7)R is involved in the initial steps of the signal transduction events leading to Panx1 activation and that a Src tyrosine kinase is likely involved in this process. Competition assays indicated that 20 microM TAT-P2X(7) peptide caused 50% reduction in Src binding to the P2X(7)R complex. Src tyrosine phosphorylation following BzATP stimulation was reduced by KN-62, TAT-P2X(7) peptide, and by the Src tyrosine inhibitor PP2 and these compounds prevented both large-conductance Panx1 currents and membrane permeabilization. These results together with the lack Panx1 tyrosine phosphorylation in response to P2X(7)R stimulation indicate the involvement of an additional molecule in the tyrosine kinase signal transduction pathway mediating Panx1 activation through the P2X(7)R.
dc.description2022-01-01
dc.formatapplication/pdf
dc.languageeng
dc.publisherAmerican Physiological Society
dc.rightsrestricted access
dc.subjectBloqueadores de junção de hiato
dc.subjectPermeabilização
dc.subjectReceptores Purinérgicos P2X7
dc.subjectgap junction blockers
dc.subjectpermeabilization
dc.subjectP2Z
dc.subjectsrc-tyrosine kinase
dc.subjectQuinases da Família src
dc.titleP2X7 receptor-Pannexin1 complex: pharmacology and signaling
dc.typeArticle


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