A differential role of macrophage TRPM2 channels in Ca²⁺ signaling and cell death in early responses to H₂O₂ - PubMed (original) (raw)

. 2013 Jul 1;305(1):C61-9.

doi: 10.1152/ajpcell.00390.2012. Epub 2013 Apr 17.

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A differential role of macrophage TRPM2 channels in Ca²⁺ signaling and cell death in early responses to H₂O₂

Jie Zou et al. Am J Physiol Cell Physiol. 2013.

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Abstract

Reactive oxygen species such as H₂O₂ elevates the cytosolic Ca²⁺ concentration ([Ca²⁺]c) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H₂O₂ activate the transient receptor potential melastatin-related 2 (TRPM2) channel as a Ca²⁺-permeable channel present in the plasma membrane or an intracellular Ca²⁺-release channel. The present study aimed to define the contribution and mechanisms of the TRPM2 channels in macrophage cells in mediating Ca²⁺ signaling and cell death during initial response to H₂O₂, using mouse peritoneal macrophage, RAW264.7, and differentiated THP-1 cells. H₂O₂ evoked robust increases in the [Ca²⁺]c, and such Ca²⁺ responses were significantly greater at body temperature than room temperature. H₂O₂-induced Ca²⁺ responses were strongly inhibited by pretreatment with PJ-34, a PARP inhibitor, and largely prevented by removal of extracellular Ca²⁺. Furthermore, H₂O₂-induced increases in the [Ca²⁺]c were completely abolished in macrophage cells isolated from trpm2-/- mice. H₂O₂ reduced macrophage cell viability in a duration- and concentration-dependent manner. H₂O₂-induced cell death was significantly attenuated by pretreatment with PJ-34 and TRPM2 channel deficiency but remained significant and persistent. Taken together, these results show that the TRPM2 channel in macrophage cells functions as a cell surface Ca²⁺-permeable channel that mediates Ca²⁺ influx and constitutes the principal Ca²⁺ signaling mechanism but has a limited, albeit significant, role in cell death during early exposure to H₂O₂.

Keywords: Ca2+ influx; ROS; TRPM2 channel; cell death; macrophage cells.

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