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Many ways to dilate the P2X7 receptor pore.

ABSTRACT: The P2X7 receptor is associated with two different membrane permeabilities: a small cation conductance which opens within milliseconds, followed by the appearance of a second channel carrying higher molecular weight compounds (including organic dyes) after prolonged agonist stimulation. This activation profile has also been found in cells expressing P2X2 and P2X4 receptors; however, the P2X7 receptor-dependent pathway has the unique ability to activate pro-inflammatory signalling in macrophages. In this issue of the BJP, Marques-da-Silva et al. demonstrate that colchicine is a potent inhibitor of both P2X7 and P2X2 receptor-dependent dye uptake, without affecting the ion channels. Colchicine also blocked the pro-inflammatory signalling downstream of P2X7 receptor activation, both in vitro and in vivo. This report suggests that the dye uptake associated with activation of P2X7 receptors is distinct from the P2X7 receptor ion channel and could be a therapeutic target for the treatment of chronic inflammation.

SUBMITTER: Pelegrin P

PROVIDER: S-EPMC3130938 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Many ways to dilate the P2X7 receptor pore.

Pelegrín Pablo P

British journal of pharmacology 20110701 5

The P2X7 receptor is associated with two different membrane permeabilities: a small cation conductance which opens within milliseconds, followed by the appearance of a second channel carrying higher molecular weight compounds (including organic dyes) after prolonged agonist stimulation. This activation profile has also been found in cells expressing P2X2 and P2X4 receptors; however, the P2X7 receptor-dependent pathway has the unique ability to activate pro-inflammatory signalling in macrophages. ...[more]

PMID: 21410461

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Project description:Epidermal growth factor (EGF), epinephrine, and the P2X7 receptor system regulate growth of human uterine cervical epithelial cells, but little is known about how these systems intercommunicate in exerting their actions. The objective of this study was to understand the mechanisms of EGF and epinephrine regulation of growth of cervical cells. Treatment of cultured CaSki cells with 0.2 nM EGF increased cell number via a PD98059-sensitive pathway. Treatment with 2 nM epinephrine increased cell number, and the effect was facilitated by cotreatment with EGF. Whereas the effect of EGF alone involved up-regulation of [3H]-thymidine incorporation and an increase in cell proliferation, the effect of epinephrine was mediated by inhibition of apoptosis. Epinephrine inhibited apoptosis induced by the P2X7 receptor ligand 2',3'-0-(4-benzoylbenzoyl)-ATP, by attenuation of P2X7 receptor plasma membrane pore formation. Cotreatment with EGF facilitated epinephrine effect via a phosphoinositide 3-kinase-dependent mechanism. CaSki cells express the beta2-adrenoceptor, and the epinephrine antiapoptotic effect could be mimicked by beta2-adrenoceptor agonists and by activators of adenylyl cyclase. Likewise, the effect could be blocked by beta2-adrenoceptor blockers and by the inhibitor of protein kinase-A H-89. Western immunoblot analysis revealed that epinephrine decreased the levels of the glycosylated 85-kDa form of the P2X7 receptor and increased receptor degradation, and that EGF potentiated these effects of epinephrine. EGF did not affect cellular levels of the beta2-adrenoceptor. In contrast, EGF, acting via the EGF receptor, augmented beta2-adrenoceptor recycling, and it inhibited beta2-adrenoceptor internalization via a phosphoinositide 3-kinase-dependent mechanism. We conclude that, in cervical epithelial cells, EGF has a dual role: as mitogen, acting via the MAPK/MAPK kinase pathway, and as an antiapoptotic factor by facilitating epinephrine effect and resulting in greater expression of beta2-adrenoceptors in the plasma membrane. These findings underscore a novel signaling network of communication between the receptor tyrosine kinases, the G protein-coupled receptors, and the purinergic P2X7 receptor.

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Many ways to dilate the P2X7 receptor pore.

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Many ways to dilate the P2X7 receptor pore.

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