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Hydrogen peroxide mobilizes Ca2+ through two distinct mechanisms in rat hepatocytes

   
@article{APS4410,
	author = {Hirohiko Sato and Teruko Takeo and Qiang Liu and Kyoko Nakano and Tomohiro Osanai and Sechiko Suga and Makoto Wakui and Jie Wu},
	title = {Hydrogen peroxide mobilizes Ca2+ through two distinct mechanisms in rat hepatocytes},
	journal = {Acta Pharmacologica Sinica},
	volume = {30},
	number = {1},
	year = {2016},
	keywords = {},
	abstract = {Aim: Hydrogen peroxide (H2O2) is produced during liver transplantation. Ischemia/reperfusion induces oxidation and causes intracellular Ca2+ overload, which harms liver cells. Our goal was to determine the precise mechanisms of these processes.
Methods: Hepatocytes were extracted from rats. Intracellular Ca2+ concentrations ([Ca2+]i), inner mitochondrial membrane potentials and NAD(P)H levels were measured using fluorescence imaging. Phospholipase C (PLC) activity was detected using exogenous PIP2. ATP concentrations were measured using the luciferin-luciferase method. Patch-clamp recordings were performed to evaluate membrane currents.
Results: H2O2 increased intracellular Ca2+ concentrations ([Ca2+]i) across two kinetic phases. A low concentration (400 μmol/L) of H2O2 induced a sustained elevation of [Ca2+]i that was reversed by removing extracellular Ca2+. H2O2 increased membrane currents consistent with intracellular ATP concentrations. The non-selective ATP-sensitive cation channel blocker amiloride inhibited H2O2-induced membrane current increases and [Ca2+]i elevation. A high concentration (1 mmol/L) of H2O2 induced an additional transient elevation of [Ca2+]i, which was abolished by the specific PLC blocker U73122 but was not eliminated by removal of extracellular Ca2+. PLC activity was increased by 1 mmol/L H2O2 but not by 400 μmol/L H2O2.
Conclusions: H2O2 mobilizes Ca2+ through two distinct mechanisms. In one, 400 μmol/L H2O2-induced sustained [Ca2+]I elevation is mediated via a Ca2+ influx mechanism, under which H2O2 impairs mitochondrial function via oxidative stress, reduces intracellular ATP production, and in turn opens ATP-sensitive, non-specific cation channels, leading to Ca2+ influx. In contrast, 1 mmol/L H2O2-induced transient elevation of [Ca2+]i is mediated via activation of the PLC signaling pathway and subsequently, by mobilization of Ca2+ from intracellular Ca2+ stores.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/4410}
}