A differential role of macrophage TRPM2 channels in Ca 2+ signaling and cell death in early responses to H 2 O 2
Reactive oxygen species such as H 2 O 2 elevates the cytosolic Ca 2+ concentration ([Ca 2+ ] c ) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H 2 O 2 activate the transient receptor potential melastatin-related 2 (TRPM2) chan...
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| Published in | American Journal of Physiology: Cell Physiology Vol. 305; no. 1; pp. C61 - C69 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
01.07.2013
|
| Online Access | Get full text |
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| Summary: | Reactive oxygen species such as H
2
O
2
elevates the cytosolic Ca
2+
concentration ([Ca
2+
]
c
) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H
2
O
2
activate the transient receptor potential melastatin-related 2 (TRPM2) channel as a Ca
2+
-permeable channel present in the plasma membrane or an intracellular Ca
2+
-release channel. The present study aimed to define the contribution and mechanisms of the TRPM2 channels in macrophage cells in mediating Ca
2+
signaling and cell death during initial response to H
2
O
2
, using mouse peritoneal macrophage, RAW264.7, and differentiated THP-1 cells. H
2
O
2
evoked robust increases in the [Ca
2+
]
c
, and such Ca
2+
responses were significantly greater at body temperature than room temperature. H
2
O
2
-induced Ca
2+
responses were strongly inhibited by pretreatment with PJ-34, a PARP inhibitor, and largely prevented by removal of extracellular Ca
2+
. Furthermore, H
2
O
2
-induced increases in the [Ca
2+
]
c
were completely abolished in macrophage cells isolated from trpm2
−/−
mice. H
2
O
2
reduced macrophage cell viability in a duration- and concentration-dependent manner. H
2
O
2
-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 Ca
2+
-permeable channel that mediates Ca
2+
influx and constitutes the principal Ca
2+
signaling mechanism but has a limited, albeit significant, role in cell death during early exposure to H
2
O
2
. |
|---|---|
| ISSN: | 0363-6143 1522-1563 |
| DOI: | 10.1152/ajpcell.00390.2012 |