Mechanisms of Mg2+ inhibition of BzATP-dependent Ca2+ responses in THP-1 monocytes

作者：Jantaratnotai Nattinee; McGeer Patrick L; McLamon James G^*

来源：Brain Research, 2012, 1442: 1-8.

DOI：10.1016/j.brainres.2012.01.004

• Mg2+
• Purinergic signaling
• P2X(7) receptor
• Store-operated Ca2+-channel

We have recently reported effects of Mg2+ to confer neuroprotection against toxicity of purinergic stimulated microglia and THP-1 monocytes. To examine mechanisms underlying neuroprotection, we have studied Mg2+ modulation of transient changes in intracellular Ca2+([Ca2+]i) in THP-1 cells induced by P2X(7)R agonist 2%26apos;,3%26apos;-[benzoyl-4-benzoyl]-ATP (BzATP). Application of BzATP caused a rapid transient increase in [Ca2+]i followed by a prolonged component. The time course of the secondary slower phase was significantly reduced with Ca2+-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 Ca2+ influx, mediated by both the P2X(7)R or by SOC, contribute to the slow component of [Ca2+]i. Treatment of THP-1 cells with 10 mM Mg2+ was highly effective in reducing the time course of BzATP-induced Ca2+ decay; unlike the other modulatory protocols, Mg2+ markedly inhibited the amplitudes of slow and rapid components. In addition, acute application of Mg2+ during BzATP-induced responses elicited in the presence of either oxATP or SKF96365 to block respective P2X(7)R and SOC contributions, rapidly attenuated [Ca2+]i to baseline levels. Priming of cells with the inflammatory stimulus LPS/IFN-gamma markedly enhanced the slower, but not rapid, phase of BzATP-induced [Ca2+]i with application of 10 mM Mg2+ 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 Mg2+ anti-inflammatory and neuroprotective actions in inflamed brain.

• 出版日期2012-3-9