Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor

Virginio, Caterina; Church, Dennis J.; North, Richard; Surprenant, Annmarie

doi:10.1016/s0028-3908(97)00141-x

Cited by 293 publications

(342 citation statements)

References 42 publications

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“…In addition, removal of Ca 2ϩ from the extracellular medium potentiated the effect of ATP on IL-1␤ release and cell death in macrophages. This is consistent with earlier reports, which showed that removal of extracellular Ca 2ϩ enhanced the effects of ATP at the P2X7 receptor (the active ligand is ATP 4Ϫ ) (24), although there is evidence to suggest that the inhibitory effect of extracellular Ca 2ϩ could be allosteric modulation of the P2X7 receptor (26). These results indicate that release of mature IL-1␤ is dependent on Ca 2ϩ release from intracellular stores rather than an influx of extracellular Ca 2ϩ .…”

Section: Discussionsupporting

confidence: 92%

Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages

Brough

Feuvre

Wheeler

et al. 2003

The Journal of Immunology

148

115

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Interleukin-1 is a primary mediator of immune responses to injury and infection, but the mechanism of its cellular release is unknown. IL-1 exists as two agonist forms (IL-1α and IL-1β) present in the cytosol of activated monocytes/macrophages. IL-1β is synthesized as an inactive precursor that lacks a signal sequence, and its trafficking does not use the classical endoplasmic reticulum-Golgi route of secretion. Using primary cultured murine peritoneal macrophages, we demonstrate that P2X7 receptor activation causes release of IL-1β and IL-1α via a common pathway, dependent upon the release of Ca2+ from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca2+ alone do not promote IL-1 secretion because a concomitant efflux of K+ through the plasmalemma is required. In addition, we demonstrate the existence of an alternative pathway for the secretion of IL-1α, independent of P2X7 receptor activation, but dependent upon Ca2+ influx. The identification of these mechanisms provides insight into the mechanism of IL-1 secretion, and may lead to the identification of targets for the therapeutic modulation of IL-1 action in inflammation.

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Section: Discussionsupporting

confidence: 92%

Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages

Brough

Feuvre

Wheeler

et al. 2003

The Journal of Immunology

148

115

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“…In human P2X 7 receptor, 1 mM Cu 2+ inhibited BzATP-induced inward current by 59.4 ± 6.8%, suggesting that the IC50 value is larger than 1 mM (18). The difference between IC 50 s of Cu 2+ in this study and those reported by Virginio et al (18) or Chessel et al (23) could be due to a difference in species or agonists used. Virginio et al (18) or Chessel et al (23) used BzATP as an agonist to study the effects of Cu 2+ on rat or human P2X7 receptor, respectively, while we used ATP to study those on mouse P2X7 receptors.…”

Section: Mode Of Inhibition By Cu 2+contrasting

confidence: 71%

“…The difference between IC 50 s of Cu 2+ in this study and those reported by Virginio et al (18) or Chessel et al (23) could be due to a difference in species or agonists used. Virginio et al (18) or Chessel et al (23) used BzATP as an agonist to study the effects of Cu 2+ on rat or human P2X7 receptor, respectively, while we used ATP to study those on mouse P2X7 receptors. Rat and human P2X 7 receptor could form a large pore (8,14), whereas mouse P2X7 receptor could not (15).…”

Section: Mode Of Inhibition By Cu 2+contrasting

confidence: 71%

“…Metal ions are known to affect various ion channels (17) including P2X receptor channels. Rat P2X7 receptor currents were inhibited by various divalent cations such as Ca 2+ , Mg 2+ (8,14), Cu 2+ , Cd 2+ , Zn 2+ , Ni 2+ , Co 2+ , Mn 2+ , Ba 2+ and Sr 2+ (18) in HEK293 cells that stably express the receptor. The effects of metal ions on the mouse P2X 7 receptor current have not been investigated in NG108-15 cells except for Mg 2+ (7).…”

mentioning

confidence: 99%

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Inhibitory Effects of Metals on ATP-Induced Current Through P2X7 Receptor in NG108-15 Cells

Watano

Matsuoka

Kimura

2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effects of heavy metal ions on the ATP-induced nonselective cation current through P2X7 receptor (INS·P2X7) in NG108-15 cells using the whole-cell patch-clamp technique. Cu 2+ inhibited the INS·P2X7 most potently among the metal ions investigated. Other metals such as Ni 2+ , Cd 2+ , Zn 2+ and Co 2+ also inhibited the INS·P2X7 in concentration-dependent manners. The order of potency was Cu 2+ >> Ni 2+ > Cd 2+ > Zn 2+ > Co 2+ with IC50 values of 16 nM, 0.79 mM, 1.2 m M, 3.0 mM and 4.6 mM, respectively. Fe 3+ (10 and 100 mM) and Mn 2+ (10 mM) did not affect the I NS · P2X7 . A high concentration of Mn 2+ (100 m M) slightly inhibited the I NS · P2X7 . When the concentration-response curve of ATP was obtained in the presence of 3 and 10 nM Cu 2+ , the maximal response but not the EC 50 value appeared to be reduced, suggesting that the inhibition is not competitive. These results suggest that under physiological and toxicological conditions, metal ions, such as Cu 2+ , Ni 2+ , Cd 2+ , Zn 2+ and Co 2+ , may modulate P2X 7 receptor channels as inhibitors. Keywords: ATP, P2X7 receptor, Nonselective cation current, Metal ion, NG108-15 cellThe P2X7 receptor is one of seven subtypes (P2X1 -7) of P2X receptors, which are ligand-gated nonselective cation channels (1, 2). It has unique properties compared to the other P2X receptors (3, 4). The P2X7 receptor requires concentrations of ATP (>0.3 mM) much higher than the other P2X (P2X 1 -6 ) receptors for activation (5). The effective form of ATP for the P2X7 receptor is the free base (ATP 4-) (6), and benzoylbenzoic ATP (BzATP) is a more potent agonist than ATP (7 -9).NG108-15 cells are hybrids of mouse neuroblastoma N18TG-2 and rat glioma C6Bu-1 cells and possess the mouse P2X 7 receptor originating from N18TG-2 cells (10). The cDNA sequence of P2X 7 receptor in NG108-15 cells was almost identical (ref. 10; I. Matsuoka, unpubished result of the full length sequence) to that of mouse P2X7 receptor first cloned by Chessell et al. (11) in NTW8 mouse microglial cells. A high concentration (>0.3 mM), but not a low concentration, of ATP activates a nonselective cation current, indicating that the only functional P2X receptor is the P2X7 receptor in NG108-15 cells (7,12,13). Rat and human P2X7 receptors transform themselves from channels to large pores by prolonged application of ATP (8,14), but this does not occur in mouse P2X7 receptors in NG108-15 cells (15). Therefore, the P2X7 receptors in NG108-15 cells are different from those in rat and human macrophages and glial cells.Metals such as vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn) and molybdenum (Mo) are essential trace elements utilized as cofactors of various enzymes (16). Metal ions are known to affect various ion channels (17) MATERIALS AND METHODS Cell cultureNG108-15 cells were grown in high-glucose Dulbecco's modified Eagle's medium supplemented with 7% fetal bovine serum, 100 mM hypoxanthine, 0.4 mM aminopterin and 16 mM thymidine...

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“…Such systems have not yet been shown to exist in mammalian cells. It has, however, been shown that P2X7 transporter is involved in uptake of divalent cations and that it is a transporter for Co uptake (Virginio et al 1997).…”

Section: Metal Ions In Cellsmentioning

confidence: 99%

Metal-on-metal hip resurfacing arthroplasty: A review of periprosthetic biological reactions

et al. 2008

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Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor

Cited by 293 publications

References 42 publications

Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages

Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages

Inhibitory Effects of Metals on ATP-Induced Current Through P2X7 Receptor in NG108-15 Cells

Metal-on-metal hip resurfacing arthroplasty: A review of periprosthetic biological reactions

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