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Title: Mechanisms of Mg<sup>2+</sup>inhibition of BzATP-dependent Ca<sup>2+</sup>responses in THP-1 monocytes
Authors: Nattinee Jantaratnotai
Patrick L. McGeer
James G. McLarnon
The University of British Columbia
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine;Neuroscience
Issue Date: 9-Mar-2012
Citation: Brain Research. Vol.1442, (2012), 1-8
Abstract: We have recently reported effects of Mg 2+ to confer neuroprotection against toxicity of purinergic stimulated microglia and THP-1 monocytes. To examine mechanisms underlying neuroprotection, we have studied Mg 2+ modulation of transient changes in intracellular Ca 2+ ([Ca 2+ ]i) in THP-1 cells induced by P2X 7 R agonist 2′,3′-[benzoyl-4-benzoyl]-ATP (BzATP). Application of BzATP caused a rapid transient increase in [Ca 2+ ]i followed by a prolonged component. The time course of the secondary slower phase was significantly reduced with Ca 2+ -free extracellular solution, with treatment of THP-1 cells by the P2X 7 R antagonist, oxATP or with exposure of cells to the store-operated channel (SOC) inhibitor, SKF96365. These results suggest that Ca 2+ influx, mediated by both the P2X 7 R or by SOC, contribute to the slow component of [Ca 2+ ]i. Treatment of THP-1 cells with 10 mM Mg 2+ was highly effective in reducing the time course of BzATP-induced Ca 2+ decay; unlike the other modulatory protocols, Mg 2+ markedly inhibited the amplitudes of slow and rapid components. In addition, acute application of Mg 2+ during BzATP-induced responses elicited in the presence of either oxATP or SKF96365 to block respective P2X 7 R and SOC contributions, rapidly attenuated [Ca 2+ ]i to baseline levels. Priming of cells with the inflammatory stimulus LPS/IFN-γ markedly enhanced the slower, but not rapid, phase of BzATP-induced [Ca 2+ ]i with application of 10 mM Mg 2+ inhibiting both components of response. A model is proposed to account for BzATP stimulation of both ionotropic P2XR and metabotropic P2YR which provides a mechanistic basis for elevated Mg 2+ anti-inflammatory and neuroprotective actions in inflamed brain. © 2012 Elsevier B.V. All rights reserved.
ISSN: 18726240
Appears in Collections:Scopus 2011-2015

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