期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 305, 期 1, 页码 C61-C69出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00390.2012
关键词
TRPM2 channel; macrophage cells; ROS; Ca2+ influx; cell death
资金
- Alzheimer's Research UK
- University of Leeds-Zhejiang University Strategic Collaboration Partnership Programme
- University of Leeds-Chinese Scholars Council PhD Scholarship
- Sino-British Fellowship Trust-Royal Society Fellowship
- Alzheimers Research UK [ART-PPG2009A-2] Funding Source: researchfish
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.
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